This joint themed section of the British Journal of Pharmacology and the British Journal of Clinical Pharmacology stems from a joint British Pharmacological Society – Italian Society of Pharmacology symposium held at the 37th National Congress of the Italian Society of Pharmacology in Naples (Italy) from 27 to 30 October 2015

Cirino, Guiseppe

Maffia, Pasquale

English

Enlighten: Publications

  
 
 
 
 
Maffia, P. and Cirino, G. (2017) Targeting inflammation to reduce 
cardiovascular disease risk. British Journal of Pharmacology, 174(22), 
pp. 3895-3897. (doi:10.1111/bph.14039) 
   
There may be differences between this version and the published 
version. You are advised to consult the publisher’s version if you wish 
to cite from it. 
 
This is the peer-reviewed version of the following article: Maffia, P. 
and Cirino, G. (2017) Targeting inflammation to reduce cardiovascular 
disease risk. British Journal of Pharmacology, 174(22), pp. 3895-3897, 
which has been published in final form at 10.1111/bph.14039. This 
article may be used for non-commercial purposes in accordance 
with Wiley Terms and Conditions for Self-Archiving. 
 
 
 
http://eprints.gla.ac.uk/148593/ 
     
 
 
 
 
 
 
Deposited on 22 September 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
  1 
EDITORIAL 
Targeting inflammation to reduce cardiovascular disease risk 
Pasquale Maffia1,2,3 and Giuseppe Cirino3 
1Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of 
Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 
2Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life 
Sciences, University of Glasgow, Glasgow, United Kingdom, 3Department of Pharmacy, 
University of Naples Federico II, Naples, Italy 
 
Correspondence Pasquale Maffia, Centre for Immunobiology, Institute of Infection, 
Immunity and Inflammation, Veterinary and Life Sciences, University of Glasgow, Glasgow, 
United Kingdom. E-mail: Pasquale.Maffia@glasgow.ac.uk and Giuseppe Cirino, Department 
of Pharmacology, University of Naples Federico II, Naples, Italy. E-mail: cirino@unina.it 
 
This joint themed issue of the British Journal of Pharmacology and the British Journal of 
Clinical Pharmacology stems from a joint British Pharmacological Society - Italian Society of 
Pharmacology symposium held at the 37th National Congress of the Italian Society of 
Pharmacology in Naples (Italy) from 27 to 30 October 2015. 
 
LINKED ARTICLES 
This article is part of a themed section on Targeting inflammation to reduce cardiovascular 
disease risk 
 
Abbreviations 
apoE-/-, apolipoprotein-E deficient mice; AT, adipose tissue; ATL, aspirin-triggered lipoxin 
A4; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; COX, 
cyclooxygenase; CVD, cardiovascular diseases; DPP4, dipeptidyl peptidase 4; H2S, hydrogen 
sulphide; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein 
cholesterol; mPGES-1, microsomal prostaglandin E synthase-1; NO, nitric oxide; NK, natural 
  2 
killer; PAR2, proteinase-activated receptor 2, PG, prostaglandin; PVAT, perivascular adipose 
tissue; tNSAIDs, traditional nonsteroidal anti-inflammatory drugs; Tsk mice, tight-skin mice. 
  
  3 
Cardiovascular diseases (CVD) are the major cause of morbidity and mortality in Western 
society and are expected to be the main cause of death globally in the near future (WHO, 
2011). Basic research data strongly support a pivotal role played by inflammatory and 
immune mechanisms in CVD and studies in animal models have shown that specific 
immune-inflammatory pathways could be targeted for therapeutic utility. However, the 
translation of this knowledge to humans is still in the early stages (Welsh et al., 2017). 
New and selective immune therapies are already in use for the treatment of autoimmune 
diseases and large clinical trials have just been published or are currently evaluating the effect 
of several of these treatments on atherosclerosis and related pathologies. The outcome of 
these studies is likely to lead to new approaches in the management of vascular inflammation. 
This joint British Journal of Pharmacology and British Journal of Clinical Pharmacology 
themed issue assembles scientists that study cardiovascular inflammation over a broad range 
of topics. The aim is to provide an up-to-date overview of the current understanding of 
inflammatory and immune mechanisms in CVD, to summarise the current clinical picture 
regarding the use of anti-inflammatory drugs in cardiovascular medicine and to discuss future 
directions towards more specific immune therapies. 
The themed issue is introduced by Paul Welsh et al. (Welsh et al., 2017). The authors provide 
an overview of the key therapeutic targets in the treatment of vascular inflammation, placing 
basic research in a wider clinical perspective. Following the publication of the review article, 
data from the Phase III Canakinumab Anti-inflammatory Thrombosis Outcomes Study 
(CANTOS: https://clinicaltrials. gov/ct2/show/NCT01327846) have been published, showing 
that canakinumab - a monoclonal antibody against IL-1β - in combination with standard 
therapy reduces recurrent cardiovascular events in people with a prior myocardial infarction 
and high levels of circulating C-reactive protein (Ridker et al., 2017). This is the first 
demonstration in a large, randomized, double blind, placebo-controlled Phase III study that 
using anti-cytokine-based therapies may be a viable approach for secondary prevention of 
atherosclerosis-related CVD. This is particularly relevant given that the use of traditional 
nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs alike is limited by 
cardiovascular toxicity as comprehensively discussed by Carlo Patrono (Patrono, 2016). He 
provides an overview of the cardiovascular effects of cyclooxygenase (COX)-2 inhibitors, 
with a focus on the mechanisms contributing to the clinical readouts of COX-2 inhibition. 
  4 
Several other key immune-mediated mechanisms in CVD could represent future options for 
therapeutic targeting and are discussed in detail in the current issue. T cell-mediated immune 
responses play a key role in ischaemic heart disease and in acute viral myocarditis 
(Stephenson et al., 2016). The authors propose that the development of novel specific 
diagnostic biomarkers could help to identify at an early stage patients who may benefit from 
immunomodulatory therapies. Andy Sage and Ziad Mallat (Sage and Mallat, 2017) discuss 
therapeutic strategies to target adaptive immunity to reduce atherosclerosis progression, such 
as regulatory T cell enhancing therapies, B cell depletion and vaccine-based approaches. 
Their work is complemented by the review from Amanda Foks and Johan Kuiper, where the 
authors discuss the therapeutic potential to control atherosclerosis through targeting a large 
variety of costimulatory and inhibitory immune checkpoint proteins (Foks and Kuiper, 2017). 
In addition, the role of cytotoxic lymphocytes such as natural killer cells, CD8+ T cells, 
natural killer (NK) T cells, γδ-T cells and human CD4+CD28- T cells in the development of 
atherosclerosis and unstable atheromas is reviewed (Kyaw et al., 2017). 
Inflammation and hypercholesterolemia are linked in a cycle where an excess of cholesterol 
accumulating in the vessel wall layers induces immune-inflammatory response(s), which in 
turn increase cholesterol deposition and accelerate pathology formation and development. 
Catapano et al. provide an overview of the crosstalk between inflammation and lipid 
metabolism, suggesting that the clinical impact of lipid-lowering drugs on inflammation is 
proportional to the reduction of low-density lipoprotein cholesterol (LDL-C) levels (Catapano 
et al., 2017). Concurrently, Iqbal et al. discuss the negative impact of systemic and vascular 
inflammation on the healthy metabolism and function of high-density lipoprotein cholesterol 
(HDL-C) (Iqbal et al., 2017). 
The contribution of perivascular adipose tissue (PVAT) to vascular inflammation has gained 
significant attention recently. Adipocytes, immune cells and fibroblasts within adipose tissue 
secrete a broad range of adipokines exerting endocrine or paracrine effects on the 
cardiovascular system. Among them, the role of adiponectin in cardiovascular pathogenesis, 
its capacity to regulate the crosstalk between adipose tissue and the cardiovascular system 
and its role as a biomarker in CVD are comprehensively discussed (Woodward et al., 2016). 
In the final review article, Cirino et al. discuss the role of gasotransmitters in vascular 
physiology and pathology (Cirino et al., 2017). The authors summarize what is currently 
known on the interconnection between nitric oxide (NO) and hydrogen sulfide (H2S), 
  5 
pointing out that addressing the molecular mechanisms underlying the interaction of these 
two gas mediators may lead to the development of new therapeutic approaches. 
The themed issue ends with five original research contributions. The work by Roviezzo et al. 
analyses the effect of proteinase-activated receptor 2 (PAR2) on aortic contraction in fibrotic 
tight-skin (Tsk) mice (Roviezzo et al., 2017). Petri et al. investigated the effect of aspirin-
triggered lipoxin A4 (ATL) and its receptor Fpr2 on atherosclerosis development and 
progression, showing anti-atherogenic effects of ATL in apolipoprotein-E (apoE)-/- mice 
(Petri et al., 2017). The selective Mas receptor agonist AVE0991 was shown to exert anti-
atherosclerotic effects by affecting monocyte/macrophage recruitment to the perivascular 
space in experimental atherosclerosis (Skiba et al., 2016). Esposito et al. demonstrated that 
the dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin preserved diastolic function in a rat 
model of heart failure with preserved ejection (Esposito et al., 2016). Finally, the effect of 
inhibitors of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) enzyme, which 
catalyses the formation of PGE2 from COX-derived PGH2, was compared in vitro on human 
vascular tone (Ozen et al., 2017). 
In summary, this joint themed issue of British Journal of Pharmacology and British Journal 
of Clinical Pharmacology will provide readers with a review of the key inflammatory and 
immune mechanisms in cardiovascular pathologies, the role of lipid and gas mediators in 
cardiovascular inflammation and the use of conventional anti-inflammatory drugs in 
cardiovascular medicine. In addition, the interplay between vascular inflammation and lipid 
metabolism, together with recent clinical trials targeting immune pathways for CVD 
prevention are comprehensively discussed. Great advances have been made in our 
understanding of immune mechanisms underlying CVD. Translation of these findings in 
clinical practice has only just begun; however, promising recent results may pave the way for 
the design of novel tissue- and or disease-specific immunomodulatory approaches to tackle 
the challenge posed by CVD on public health. 
 
Nomenclature of Targets and Ligands 
Key protein targets and ligands in this article are hyperlinked to corresponding entries in 
http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS 
Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the 
Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015). 
  6 
 
Acknowledgements 
We thank all authors who contributed to this Research Topic. This work was funded by the 
British Heart Foundation grants PG/12/81/29897 and RE/13/5/30177; the European 
Commission Marie Skłodowska-Curie Individual Fellowships 661369; the EPSRC grant 
EP/L014165/1; and the Tenovus Scotland PROJECT S15/24. 
 
Conflict of Interest 
The authors wish to acknowledge that they are co‐ authors of the articles by Welsh et al. 
(2017), Cirino et al. (2017) and Roviezzo et al. (2016) in this issue. They have also co-
authored papers with Andrew Sage, Ziad Mallat, Liberato Berrino, Francesco Rossi, 
Antonella De Angelis and Konrad Urbanek. 
  
  7 
References 
Alexander SP, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. (2015). The 
Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors. Br J Pharmacol 172(24): 
5979-6023. 
Alexander SP, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. (2015). The 
Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172(24): 6024-
109. 
Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, et al. (2015). The 
Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol 172(24): 5729-
43. 
Catapano AL, Pirillo A, Norata GD (2017). Vascular inflammation and low-density 
lipoproteins: is cholesterol the link? A lesson from the clinical trials. Br J Pharmacol 2016 
Mar 30. doi: 10.1111/bph.13805. [Epub ahead of print]. 
Cirino G, Vellecco V, Bucci M (2017). Nitric oxide and hydrogen sulfide: the gasotransmitter 
paradigm of the vascular system. Br J Pharmacol 2017 Apr 13. doi: 10.1111/bph.13815. 
[Epub ahead of print]. 
Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, et al. (2016). 
Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of 
heart failure with preserved ejection fraction. Br J Pharmacol 2016 Dec 6. doi: 
10.1111/bph.13686. [Epub ahead of print]. 
Foks AC, Kuiper J (2017). Immune checkpoint proteins: exploring their therapeutic potential 
to regulate atherosclerosis. Br J Pharmacol 2017 Mar 30. doi: 10.1111/bph.13802. [Epub 
ahead of print]. 
Iqbal F, Baker WS, Khan MI, Thukuntla S, McKinney KH, Abate N, et al. (2017). Current 
and future therapies for addressing the effects of inflammation on HDL cholesterol 
metabolism. Br J Pharmacol 2017 Mar 22. doi: 10.1111/bph.13743. [Epub ahead of print]. 
Kyaw T, Peter K, Li Y, Tipping P, Toh BH, Bobik A (2017). Cytotoxic lymphocytes and 
atherosclerosis: significance, mechanisms and therapeutic challenges. Br J Pharmacol 2017 
May 4. doi: 10.1111/bph.13845. [Epub ahead of print]. 
Ozen G, Gomez I, Daci A, Deschildre C, Boubaya L, Teskin O, et al. (2017). mPGES-1 
inhibitor reduces human vascular tone by increasing PGI(2) : a safer alternative to COXIBs. 
  8 
Br J Pharmacol 2017 Jul 3. doi: 10.1111/bph.13939. [Epub ahead of print]. 
Patrono C (2016). Cardiovascular effects of cyclooxygenase-2 inhibitors: a mechanistic and 
clinical perspective. Br J Clin Pharmacol 82(4):957-64. 
Petri MH, Laguna-Fernandez A, Arnardottir H, Wheelock CE, Perretti M, Hansson GK, et al. 
(2017). Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein 
E(-/-) mice. Br J Pharmacol 2017 Jan 10. doi: 10.1111/bph.13707. [Epub ahead of print]. 
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. (2017). 
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 
2017 Aug 27. doi: 10.1056/NEJMoa1707914. [Epub ahead of print]. 
Roviezzo F, Brancaleone V, Mattera Iacono V, Bertolino A, De Cunto G, Vellecco V, et al. 
(2016). Proteinase activated receptor-2 counterbalances the vascular effects of endothelin-1 
in fibrotic tight-skin mice. Br J Pharmacol 2016 Sep 14. doi: 10.1111/bph.13618. [Epub 
ahead of print]. 
Sage AP, Mallat Z (2017). Readapting the adaptive immune response - therapeutic strategies 
for atherosclerosis. Br J Pharmacol 2017 Jan 4. doi: 10.1111/bph.13700. [Epub ahead of 
print]. 
Skiba DS, Nosalski R, Mikolajczyk TP, Siedlinski M, Rios FJ, Montezano AC, et al. (2016). 
Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition 
of perivascular and plaque inflammation in early atherosclerosis. Br J Pharmacol 2016 Dec 9. 
doi: 10.1111/bph.13685. [Epub ahead of print]. 
Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP et al. (2016). 
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative 
interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 44: D1054-1068. 
Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM (2016). T-cell immunity in 
myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol 
2016 Sep 2. doi: 10.1111/bph.13613. [Epub ahead of print]. 
Welsh P, Grassia G, Botha S, Sattar N, Maffia P (2017). Targeting inflammation to reduce 
cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol 2017 Apr 13. doi: 
10.1111/bph.13818. [Epub ahead of print]. 
Woodward L, Akoumianakis I, Antoniades C (2016). Unravelling the adiponectin paradox: 
novel roles of adiponectin in the regulation of cardiovascular disease. Br J Pharmacol 2016 
  9 
Sep 15. doi: 10.1111/bph.13619. [Epub ahead of print]. 
World Health Organization (WHO) (2011). Global status report on noncommunicable 
diseases 2010. ISBN: 978 92 4 156422 9. 


Targeting inflammation to reduce cardiovascular disease risk

Enlighten

      Maffia, P. and Cirino, G. (2017) Targeting inflammation to reduce cardiovascular disease risk. British Journal of Pharmacology, 174(22), pp. 3895-3897. (doi:10.1111/bph.14039)    There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.  This is the peer-reviewed version of the following article: Maffia, P. and Cirino, G. (2017) Targeting inflammation to reduce cardiovascular disease risk. British Journal of Pharmacology, 174(22), pp. 3895-3897, which has been published in final form at 10.1111/bph.14039. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.    http://eprints.gla.ac.uk/148593/            Deposited on 22 September 2017                 Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk   1 EDITORIAL Targeting inflammation to reduce cardiovascular disease risk Pasquale Maffia1,2,3 and Giuseppe Cirino3 1Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 2Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 3Department of Pharmacy, University of Naples Federico II, Naples, Italy  Correspondence Pasquale Maffia, Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. E-mail: Pasquale.Maffia@glasgow.ac.uk and Giuseppe Cirino, Department of Pharmacology, University of Naples Federico II, Naples, Italy. E-mail: cirino@unina.it  This joint themed issue of the British Journal of Pharmacology and the British Journal of Clinical Pharmacology stems from a joint British Pharmacological Society - Italian Society of Pharmacology symposium held at the 37th National Congress of the Italian Society of Pharmacology in Naples (Italy) from 27 to 30 October 2015.  LINKED ARTICLES This article is part of a themed section on Targeting inflammation to reduce cardiovascular disease risk  Abbreviations apoE-/-, apolipoprotein-E deficient mice; AT, adipose tissue; ATL, aspirin-triggered lipoxin A4; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; COX, cyclooxygenase; CVD, cardiovascular diseases; DPP4, dipeptidyl peptidase 4; H2S, hydrogen sulphide; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; mPGES-1, microsomal prostaglandin E synthase-1; NO, nitric oxide; NK, natural   2 killer; PAR2, proteinase-activated receptor 2, PG, prostaglandin; PVAT, perivascular adipose tissue; tNSAIDs, traditional nonsteroidal anti-inflammatory drugs; Tsk mice, tight-skin mice.     3 Cardiovascular diseases (CVD) are the major cause of morbidity and mortality in Western society and are expected to be the main cause of death globally in the near future (WHO, 2011). Basic research data strongly support a pivotal role played by inflammatory and immune mechanisms in CVD and studies in animal models have shown that specific immune-inflammatory pathways could be targeted for therapeutic utility. However, the translation of this knowledge to humans is still in the early stages (Welsh et al., 2017). New and selective immune therapies are already in use for the treatment of autoimmune diseases and large clinical trials have just been published or are currently evaluating the effect of several of these treatments on atherosclerosis and related pathologies. The outcome of these studies is likely to lead to new approaches in the management of vascular inflammation. This joint British Journal of Pharmacology and British Journal of Clinical Pharmacology themed issue assembles scientists that study cardiovascular inflammation over a broad range of topics. The aim is to provide an up-to-date overview of the current understanding of inflammatory and immune mechanisms in CVD, to summarise the current clinical picture regarding the use of anti-inflammatory drugs in cardiovascular medicine and to discuss future directions towards more specific immune therapies. The themed issue is introduced by Paul Welsh et al. (Welsh et al., 2017). The authors provide an overview of the key therapeutic targets in the treatment of vascular inflammation, placing basic research in a wider clinical perspective. Following the publication of the review article, data from the Phase III Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS: https://clinicaltrials. gov/ct2/show/NCT01327846) have been published, showing that canakinumab - a monoclonal antibody against IL-1β - in combination with standard therapy reduces recurrent cardiovascular events in people with a prior myocardial infarction and high levels of circulating C-reactive protein (Ridker et al., 2017). This is the first demonstration in a large, randomized, double blind, placebo-controlled Phase III study that using anti-cytokine-based therapies may be a viable approach for secondary prevention of atherosclerosis-related CVD. This is particularly relevant given that the use of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs alike is limited by cardiovascular toxicity as comprehensively discussed by Carlo Patrono (Patrono, 2016). He provides an overview of the cardiovascular effects of cyclooxygenase (COX)-2 inhibitors, with a focus on the mechanisms contributing to the clinical readouts of COX-2 inhibition.   4 Several other key immune-mediated mechanisms in CVD could represent future options for therapeutic targeting and are discussed in detail in the current issue. T cell-mediated immune responses play a key role in ischaemic heart disease and in acute viral myocarditis (Stephenson et al., 2016). The authors propose that the development of novel specific diagnostic biomarkers could help to identify at an early stage patients who may benefit from immunomodulatory therapies. Andy Sage and Ziad Mallat (Sage and Mallat, 2017) discuss therapeutic strategies to target adaptive immunity to reduce atherosclerosis progression, such as regulatory T cell enhancing therapies, B cell depletion and vaccine-based approaches. Their work is complemented by the review from Amanda Foks and Johan Kuiper, where the authors discuss the therapeutic potential to control atherosclerosis through targeting a large variety of costimulatory and inhibitory immune checkpoint proteins (Foks and Kuiper, 2017). In addition, the role of cytotoxic lymphocytes such as natural killer cells, CD8+ T cells, natural killer (NK) T cells, γδ-T cells and human CD4+CD28- T cells in the development of atherosclerosis and unstable atheromas is reviewed (Kyaw et al., 2017). Inflammation and hypercholesterolemia are linked in a cycle where an excess of cholesterol accumulating in the vessel wall layers induces immune-inflammatory response(s), which in turn increase cholesterol deposition and accelerate pathology formation and development. Catapano et al. provide an overview of the crosstalk between inflammation and lipid metabolism, suggesting that the clinical impact of lipid-lowering drugs on inflammation is proportional to the reduction of low-density lipoprotein cholesterol (LDL-C) levels (Catapano et al., 2017). Concurrently, Iqbal et al. discuss the negative impact of systemic and vascular inflammation on the healthy metabolism and function of high-density lipoprotein cholesterol (HDL-C) (Iqbal et al., 2017). The contribution of perivascular adipose tissue (PVAT) to vascular inflammation has gained significant attention recently. Adipocytes, immune cells and fibroblasts within adipose tissue secrete a broad range of adipokines exerting endocrine or paracrine effects on the cardiovascular system. Among them, the role of adiponectin in cardiovascular pathogenesis, its capacity to regulate the crosstalk between adipose tissue and the cardiovascular system and its role as a biomarker in CVD are comprehensively discussed (Woodward et al., 2016). In the final review article, Cirino et al. discuss the role of gasotransmitters in vascular physiology and pathology (Cirino et al., 2017). The authors summarize what is currently known on the interconnection between nitric oxide (NO) and hydrogen sulfide (H2S),   5 pointing out that addressing the molecular mechanisms underlying the interaction of these two gas mediators may lead to the development of new therapeutic approaches. The themed issue ends with five original research contributions. The work by Roviezzo et al. analyses the effect of proteinase-activated receptor 2 (PAR2) on aortic contraction in fibrotic tight-skin (Tsk) mice (Roviezzo et al., 2017). Petri et al. investigated the effect of aspirin-triggered lipoxin A4 (ATL) and its receptor Fpr2 on atherosclerosis development and progression, showing anti-atherogenic effects of ATL in apolipoprotein-E (apoE)-/- mice (Petri et al., 2017). The selective Mas receptor agonist AVE0991 was shown to exert anti-atherosclerotic effects by affecting monocyte/macrophage recruitment to the perivascular space in experimental atherosclerosis (Skiba et al., 2016). Esposito et al. demonstrated that the dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin preserved diastolic function in a rat model of heart failure with preserved ejection (Esposito et al., 2016). Finally, the effect of inhibitors of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) enzyme, which catalyses the formation of PGE2 from COX-derived PGH2, was compared in vitro on human vascular tone (Ozen et al., 2017). In summary, this joint themed issue of British Journal of Pharmacology and British Journal of Clinical Pharmacology will provide readers with a review of the key inflammatory and immune mechanisms in cardiovascular pathologies, the role of lipid and gas mediators in cardiovascular inflammation and the use of conventional anti-inflammatory drugs in cardiovascular medicine. In addition, the interplay between vascular inflammation and lipid metabolism, together with recent clinical trials targeting immune pathways for CVD prevention are comprehensively discussed. Great advances have been made in our understanding of immune mechanisms underlying CVD. Translation of these findings in clinical practice has only just begun; however, promising recent results may pave the way for the design of novel tissue- and or disease-specific immunomodulatory approaches to tackle the challenge posed by CVD on public health.  Nomenclature of Targets and Ligands Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015).   6  Acknowledgements We thank all authors who contributed to this Research Topic. This work was funded by the British Heart Foundation grants PG/12/81/29897 and RE/13/5/30177; the European Commission Marie Skłodowska-Curie Individual Fellowships 661369; the EPSRC grant EP/L014165/1; and the Tenovus Scotland PROJECT S15/24.  Conflict of Interest The authors wish to acknowledge that they are co‐ authors of the articles by Welsh et al. (2017), Cirino et al. (2017) and Roviezzo et al. (2016) in this issue. They have also co-authored papers with Andrew Sage, Ziad Mallat, Liberato Berrino, Francesco Rossi, Antonella De Angelis and Konrad Urbanek.     7 References Alexander SP, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors. Br J Pharmacol 172(24): 5979-6023. Alexander SP, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172(24): 6024-109. Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol 172(24): 5729-43. Catapano AL, Pirillo A, Norata GD (2017). Vascular inflammation and low-density lipoproteins: is cholesterol the link? A lesson from the clinical trials. Br J Pharmacol 2016 Mar 30. doi: 10.1111/bph.13805. [Epub ahead of print]. Cirino G, Vellecco V, Bucci M (2017). Nitric oxide and hydrogen sulfide: the gasotransmitter paradigm of the vascular system. Br J Pharmacol 2017 Apr 13. doi: 10.1111/bph.13815. [Epub ahead of print]. Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, et al. (2016). Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. Br J Pharmacol 2016 Dec 6. doi: 10.1111/bph.13686. [Epub ahead of print]. Foks AC, Kuiper J (2017). Immune checkpoint proteins: exploring their therapeutic potential to regulate atherosclerosis. Br J Pharmacol 2017 Mar 30. doi: 10.1111/bph.13802. [Epub ahead of print]. Iqbal F, Baker WS, Khan MI, Thukuntla S, McKinney KH, Abate N, et al. (2017). Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism. Br J Pharmacol 2017 Mar 22. doi: 10.1111/bph.13743. [Epub ahead of print]. Kyaw T, Peter K, Li Y, Tipping P, Toh BH, Bobik A (2017). Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges. Br J Pharmacol 2017 May 4. doi: 10.1111/bph.13845. [Epub ahead of print]. Ozen G, Gomez I, Daci A, Deschildre C, Boubaya L, Teskin O, et al. (2017). mPGES-1 inhibitor reduces human vascular tone by increasing PGI(2) : a safer alternative to COXIBs.   8 Br J Pharmacol 2017 Jul 3. doi: 10.1111/bph.13939. [Epub ahead of print]. Patrono C (2016). Cardiovascular effects of cyclooxygenase-2 inhibitors: a mechanistic and clinical perspective. Br J Clin Pharmacol 82(4):957-64. Petri MH, Laguna-Fernandez A, Arnardottir H, Wheelock CE, Perretti M, Hansson GK, et al. (2017). Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E(-/-) mice. Br J Pharmacol 2017 Jan 10. doi: 10.1111/bph.13707. [Epub ahead of print]. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. (2017). Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017 Aug 27. doi: 10.1056/NEJMoa1707914. [Epub ahead of print]. Roviezzo F, Brancaleone V, Mattera Iacono V, Bertolino A, De Cunto G, Vellecco V, et al. (2016). Proteinase activated receptor-2 counterbalances the vascular effects of endothelin-1 in fibrotic tight-skin mice. Br J Pharmacol 2016 Sep 14. doi: 10.1111/bph.13618. [Epub ahead of print]. Sage AP, Mallat Z (2017). Readapting the adaptive immune response - therapeutic strategies for atherosclerosis. Br J Pharmacol 2017 Jan 4. doi: 10.1111/bph.13700. [Epub ahead of print]. Skiba DS, Nosalski R, Mikolajczyk TP, Siedlinski M, Rios FJ, Montezano AC, et al. (2016). Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. Br J Pharmacol 2016 Dec 9. doi: 10.1111/bph.13685. [Epub ahead of print]. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP et al. (2016). The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 44: D1054-1068. Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM (2016). T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol 2016 Sep 2. doi: 10.1111/bph.13613. [Epub ahead of print]. Welsh P, Grassia G, Botha S, Sattar N, Maffia P (2017). Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol 2017 Apr 13. doi: 10.1111/bph.13818. [Epub ahead of print]. Woodward L, Akoumianakis I, Antoniades C (2016). Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease. Br J Pharmacol 2016   9 Sep 15. doi: 10.1111/bph.13619. [Epub ahead of print]. World Health Organization (WHO) (2011). Global status report on noncommunicable diseases 2010. ISBN: 978 92 4 156422 9. 

Pasquale Maffia

Giuseppe Cirino

Archivio della ricerca - Università degli studi di Napoli Federico II

Themed Section: Targeting Inflammation to Reduce Cardiovascular Disease RiskEDITORIALTargeting inflammation to reducecardiovascular disease riskCorrespondence Pasquale Maffia, Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical,Veterinary and Life Sciences, University of Glasgow, Glasgow, UK and Giuseppe Cirino, Department of Pharmacy, University of NaplesFederico II, Naples, Italy. E-mail: pasquale.maffia@glasgow.ac.uk; cirino@unina.itPasquale Maffia1,2,3 and Giuseppe Cirino31Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University ofGlasgow, Glasgow, UK, 2Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow,Glasgow, UK, and 3Department of Pharmacy, University of Naples Federico II, Naples, ItalyThis joint themed section of the British Journal of Pharmacology and the British Journal of Clinical Pharmacology stems from a jointBritish Pharmacological Society – Italian Society of Pharmacology symposium held at the 37th National Congress of the ItalianSociety of Pharmacology in Naples (Italy) from 27 to 30 October 2015.LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articlesin this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetocAbbreviationsAT, adipose tissue; ATL, aspirin-triggered lipoxin A4; CVDs, cardiovascular diseasesCardiovascular diseases (CVDs) are the major cause of mor-bidity and mortality in Western society and, in the near future,are expected to be the main cause of death globally (WHO,2011). Basic research data strongly support a crucial role playedby inflammatory and immunemechanisms inCVD, and studiesin animal models have shown that specific immune-inflamma-tory pathways could be targeted for therapeutic utility. However,the translation of this scientific knowledge to the treatment ofhuman CVDs is still in the early stages (Welsh et al., 2017).New and selective immune therapies are already in use forthe treatment of autoimmune diseases, and large clinical trialshave just been published or are currently evaluating the effectof several of these treatments on atherosclerosis and related pa-thologies. The outcome of these studies is likely to lead to newapproaches in the management of vascular inflammation.This joint themed section of the British Journal of Pharmacol-ogy and the British Journal of Clinical Pharmacology has broughttogether scientists studying cardiovascular inflammationover a broad range of topics. The aim is to provide an up-to-date overview of the current understanding of inflammatoryand immune mechanisms in CVD, to summarize the currentclinical picture regarding the use of anti-inflammatory drugsin cardiovascular medicine and to discuss future directionstowards more specific immune therapies.The themed section is introduced by Welsh et al. (2017).These authors provide an overview of the key therapeutictargets in the treatment of vascular inflammation, placingbasic research in a wider clinical perspective. Following thepublication of the review article, data from the Phase IIICanakinumab Anti-inflammatory Thrombosis OutcomesStudy (https://clinicaltrials.gov/ct2/show/NCT01327846)have been published, showing that canakinumab – amonoclonal antibody against IL-1β – in combination withstandard therapy reduces recurrent cardiovascular events inpatients with a prior myocardial infarction and high levelsBJP British Journal ofPharmacologyBritish Journal of Pharmacology (2017) 174 3895–3897 3895DOI:10.1111/bph.14039© 2017 The British Pharmacological Societyof circulating C-reactive protein (Ridker et al., 2017). Thisis the first demonstration in a large, randomized,double-blind, placebo-controlled phase III study that usinganti-cytokine-based therapies may be a viable approach for sec-ondary prevention of atherosclerosis-related CVD. This is par-ticularly relevant given that the use of traditional non-steroidal anti-inflammatory drugs and coxibs alike is limitedby cardiovascular toxicity, as comprehensively discussed byPatrono (2016). He provides an overview of the cardiovasculareffects of COX-2 inhibitors, with a focus on the mechanismscontributing to the clinical readouts of COX-2 inhibition.Several other key immune-mediated mechanisms in CVDcould represent future options for therapeutic targeting andare discussed in detail in this issue. T-cell-mediated immuneresponses play a key role in ischaemic heart disease and inacute viral myocarditis (Stephenson et al., 2017). The authorspropose that the development of novel-specific diagnosticbiomarkers could help to identify at an early stage patientswho may benefit from immunomodulatory therapies. Sageand Mallat (2017) discuss therapeutic strategies to targetadaptive immunity to reduce atherosclerosis progression,such as regulatory T-cell enhancing therapies, B-cell deple-tion and vaccine-based approaches. Their work iscomplemented by the review from Foks and Kuiper (2017),where the authors discuss the therapeutic potential to controlatherosclerosis through targeting a large variety of co-stimu-latory and inhibitory immune checkpoint proteins. In addi-tion, the role of cytotoxic lymphocytes such as NK cells,CD8+ T-cells, NK T-cells, γδ T-cells and human CD4+CD28T-cells in the development of atherosclerosis and unstableatheromas is reviewed (Kyaw et al., 2017).Inflammation and hypercholesterolaemia are linked in acycle where an excess of cholesterol accumulating in thevessel wall layers induces immune-inflammatory response(s),which in turn increase cholesterol deposition and acceleratepathology formation and development. Catapano et al.(2017) provide an overview of the crosstalk between inflam-mation and lipid metabolism, suggesting that the clinical im-pact of lipid-lowering drugs on inflammation is proportionalto the reduction of LDL cholesterol levels. Concurrently,Iqbal et al. (2017) discuss the negative impact of systemicand vascular inflammation on the healthy metabolism andfunction of HDL cholesterol.The contribution of perivascular adipose tissue (AT) tovascular inflammation has gained significant attentionrecently. Adipocytes, immune cells and fibroblasts withinAT secrete a broad range of adipokines exerting endocrine orparacrine effects on the cardiovascular system. Among them,the role of adiponectin in cardiovascular pathogenesis, itscapacity to regulate the crosstalk between AT and thecardiovascular system and its role as a biomarker in CVD iscomprehensively discussed (Woodward et al., 2017).In the final review article, Cirino et al. (2017) discuss the roleof gasotransmitters in vascular physiology and pathology. Theauthors summarize what is currently known on the intercon-nection betweenNO andhydrogen sulfide, pointing out thataddressing the molecular mechanisms underlying the interac-tion of these two gaseous mediators may lead to the develop-ment of new therapeutic approaches.The themed section ends with five original researchcontributions. The work by Roviezzo et al. (2017) analysesthe effect of proteinase-activated receptor 2 on aorticcontraction in fibrotic tight-skin mice. Petri et al. (2017) in-vestigated the effect of aspirin-triggered lipoxin A4(ATL) and its receptor Fpr2 on atherosclerosis developmentand progression, showing anti-atherogenic effects of ATL inapolipoprotein E-deficient mice. The selectiveMas receptoragonist AVE0991 was shown to exert anti-atheroscleroticeffects by affecting monocyte/macrophage recruitment tothe perivascular space in experimental atherosclerosis(Skiba et al., 2017). Esposito et al. (2017) demonstrated that thedipeptidyl peptidase 4 inhibitor sitagliptin preserved dia-stolic function in a ratmodel of heart failurewith preserved ejec-tion. Finally, the effect of inhibitors of COX-2 and microsomalPGE synthase-1 enzyme, which catalyses the formation ofPGE2 from COX-derived PGH2, was compared in vitro, on hu-man vascular tone (Ozen et al., 2017).In summary, this joint themed section of the BritishJournal of Pharmacology and the British Journal of ClinicalPharmacology will provide readers with a review of the keyinflammatory and immune mechanisms in cardiovascularpathologies, the role of lipid and gas mediators in cardio-vascular inflammation and the use of conventional anti-in-flammatory drugs in cardiovascular medicine. In addition,the interplay between vascular inflammation and lipid me-tabolism, together with recent clinical trials targeting im-mune pathways for CVD prevention, is comprehensivelydiscussed. Great advances have been made in our under-standing of immune mechanisms underlying CVD. Transla-tion of these findings in clinical practice has only justbegun. However, promising recent results may pave the wayfor the design of novel tissue-specific and or disease-specificimmunomodulatory approaches to tackle the challengeposed by CVD for public health.Nomenclature of targets and ligandsKey protein targets and ligands in this article are hyperlinked tocorresponding entries in http://www.guidetopharmacology.org,the common portal for data from the IUPHAR/BPS Guide toPHARMACOLOGY (Southan et al., 2016), and are permanentlyarchived in the Concise Guide to PHARMACOLOGY 2015/16(Alexander et al., 2015a,b,c).AcknowledgementsWe thank all authors who contributed to this research topic.This work was funded by the British Heart Foundation grantsPG/12/81/29897 and RE/13/5/30177, the European Commis-sion Marie Skłodowska-Curie Individual Fellowships 661369,the EPSRC grant EP/L014165/1 and the Tenovus ScotlandProject S15/24.Conflict of interestThe authors wish to acknowledge that they are co-authors ofthe articles by Welsh et al. (2017), Cirino et al. (2017) andRoviezzo et al. (2017) in this issue. They have also co-authored papers with Andrew Sage, Ziad Mallat, LiberatoBerrino, Francesco Rossi, Antonella De Angelis and KonradUrbanek.BJP P Maffia and G Cirino3896 British Journal of Pharmacology (2017) 174 3895–3897ReferencesAlexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda Eet al. (2015a). The Concise Guide to PHARMACOLOGY 2015/16:Overview. Br J Pharmacol 172: 5729–5743.Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HEet al. (2015b). The Concise Guide to PHARMACOLOGY 2015/16:Catalytic receptors. Br J Pharmacol 172: 5979–6023.Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HEet al. (2015c). The Concise Guide to PHARMACOLOGY 2015/16:Enzymes. Br J Pharmacol 172: 6024–6109.Catapano AL, Pirillo A, Norata GD (2017). Vascular inflammation andlow-density lipoproteins: is cholesterol the link? A lesson from theclinical trials. Br J Pharmacol 174: 3973–3985.Cirino G, Vellecco V, Bucci M (2017). Nitric oxide and hydrogensulfide: the gasotransmitter paradigm of the vascular system. Br JPharmacol 174: 4021–4031.Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo Fet al. (2017). Sitagliptin reduces inflammation, fibrosis and preservesdiastolic function in a rat model of heart failure with preservedejection fraction. Br J Pharmacol 174: 4070–4086.Foks AC, Kuiper J (2017). Immune checkpoint proteins: exploringtheir therapeutic potential to regulate atherosclerosis. Br J Pharmacol174: 3940–3955.Iqbal F, BakerWS, KhanMI, Thukuntla S, McKinney KH, Abate N et al.(2017). Current and future therapies for addressing the effects ofinflammation on HDL cholesterol metabolism. Br J Pharmacol 174:3986–4006.Kyaw T, Peter K, Li Y, Tipping P, Toh BH, Bobik A (2017). Cytotoxiclymphocytes and atherosclerosis: significance, mechanisms andtherapeutic challenges. Br J Pharmacol 174: 3956–3972.Ozen G, Gomez I, Daci A, Deschildre C, Boubaya L, Teskin O et al.(2017). Inhibition of microsomal PGE synthase-1 reduces humanvascular tone by increasing PGI2: a safer alternative to COX-2inhibition. Br J Pharmacol 174: 4087–4098.Patrono C (2016). Cardiovascular effects of cyclooxygenase-2inhibitors: a mechanistic and clinical perspective. Br J ClinPharmacol 82: 957–964.Petri MH, Laguna-Fernandez A, Arnardottir H, Wheelock CE, PerrettiM, Hansson GK et al. (2017). Aspirin-triggered lipoxin A4 inhibitsatherosclerosis progression in apolipoprotein E/ mice. Br JPharmacol 174: 4043–4054.Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH,Ballantyne C et al. (2017). Antiinflammatory therapy withcanakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131.Roviezzo F, Brancaleone V, Mattera Iacono V, Bertolino A, De CuntoG, Vellecco Vet al. (2017). Proteinase activated receptor-2counterbalances the vascular effects of endothelin-1 in fibrotic tight-skin mice. Br J Pharmacol 174: 4032–4042.Sage AP, Mallat Z (2017). Readapting the adaptive immune response –therapeutic strategies for atherosclerosis. Br J Pharmacol 174:3926–3939.Skiba DS, Nosalski R, Mikolajczyk TP, Siedlinski M, Rios FJ,Montezano AC et al. (2017). Anti-atherosclerotic effect of theangiotensin 1-7 mimetic AVE0991 is mediated by inhibition ofperivascular and plaque inflammation in early atherosclerosis. Br JPharmacol 174: 4055–4069.Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ,Alexander SPH et al. (2016). The IUPHAR/BPS Guide toPHARMACOLOGY in 2016: towards curated quantitativeinteractions between 1300 protein targets and 6000 ligands. NuclAcids Res 44: D1054–D1068.Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM (2017).T-cell immunity in myocardial inflammation: pathogenic role andtherapeutic manipulation. Br J Pharmacol 174: 3914–3925.Welsh P, Grassia G, Botha S, Sattar N, Maffia P (2017). Targetinginflammation to reduce cardiovascular disease risk: a realistic clinicalprospect? Br J Pharmacol 174: 3898–3913.Woodward L, Akoumianakis I, Antoniades C (2017). Unravelling theadiponectin paradox: novel roles of adiponectin in the regulation ofcardiovascular disease. Br J Pharmacol 174: 4007–4020.World Health Organization (WHO) (2011). Global status report onnoncommunicable diseases 2010. ISBN: 9789241564229.Editorial BJPBritish Journal of Pharmacology (2017) 174 3895–3897 3897

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Archivio della ricerca - Università degli studi di Napoli Federico II