Emerging small molecule drugs

Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208

Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δ mRNA (p=0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p=0.026 and p=0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p=0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy

0312: Characterization of human valvular interstitial cells isolated from normal and fibrocalcified aortic valves

PurposeAortic Valve Stenosis (AVS) affects 2% to 6% of population over 65 years in industrialized countries. This atherosclerosis-like pathology involves Valve Interstitial Cell (VIC) proliferation and commitment to osteoblast- like cells. This prevalent cell type of aortic valve presents five identifiable phenotypes: embryonic progenitor endothelial/mesenchymal cells, progenitor, quiescent, activated and osteoblastic VICs. To study the pathophysiology of AVS, their in vitro cultures are frequently used. Our purpose is to characterize VICs isolated from normal and fibrocalcified human aortic valves and analyze their in vitro behavior.MethodsWe collected 5 normal and 5 fibrocalcified human aortic valves. VICs were isolated by collagenase digestion. Characterization is assessed at different passages (2 to 5) by immunofluorescence. Analyzed markers consist of progenitor cell markers (SSEA4, ABCG2, CD90, NG2 and OsteoBlast CaDHerin (OB-CDH)), fibroblast markers (vimentin and HSP47) and smooth muscle cell (SMC) marker (α-actin). By blue trypan and MTS, we compared the viability and proliferation of VICs in standard and starvation medium at 48 hours.ResultsIndependently of their origin, VICs express all progenitor cell markers. Fibroblasts markers are expressed twice more by pathological VICs and four times more for SMC marker. In standard medium, VICs viability is similar (96,7±2,4% vs 96,4±2,3% ; normal vs pathological ± SEM). Pathological VICs proliferate more than normal VICs (2,2±0,7 vs 1,6±0,4 ; OD/OD control). In starvation medium, viability is significantly reduced for pathological VICs (89,6±7,9% vs 76,5±5,3%) but still proliferate in opposition with normal VICs (1,7±0,6 vs 1,2±0,3).ConclusionAll VICs phenotypes are found in vitro with no culture selection but in different ratios according to their origin. These new data in VICs isolated from normal or pathological human aortic valves allow us to approve their use in vitro

11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis

11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74–76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.—Kipari, T., Hadoke, P. W. F., Iqbal, J., Man, T. Y., Miller, E., Coutinho, A. E., Zhang, Z., Sullivan, K. M., Mitic, T., Livingstone, D. E. W., Schrecker, C., Samuel, K., White, C. I., Bouhlel, M. A., Chinetti-Gbaguidi, G., Staels, B., Andrew, R., Walker, B. R., Savill, J. S., Chapman, K. E., Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis

PPARbeta in macrophages and atherosclerosis

International audienceMacrophages are central cells in the genesis and development of atherosclerosis, one of themajor causes of cardiovascular diseases. Macrophages take up lipids (mainly cholesterol andtriglycerides) from lipoproteins thus transforming into foam cells. Moreover, through theefflux pathway, macrophages are the main actors of the elimination of excessive tissuecholesterol toward extra-cellular acceptors. Macrophages participate in the control ofinflammation by displaying different functional phenotypes, from the M1 pro-inflammatoryto the M2 anti-inflammatory state.The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta (also calledPPARdelta or PPARbeta/delta) is expressed in macrophages where it plays a different role in the controlof lipid metabolism, inflammation and phagocytosis of apoptotic cells.This review will summarize our current understanding of how PPARbeta regulates macrophagebiology and its impact on atherosclerosis. Differences between studies and species-specificmacrophage gene regulation will be discussed

Macrophage polarization in metabolic disorders: functions and regulation.

International audiencePURPOSE OF REVIEW: To discuss recent findings on the role and regulation of macrophage polarization in obesity and atherosclerosis. RECENT FINDINGS: Macrophages infiltrate the vascular wall during atherosclerosis and adipose tissue during obesity. At least two distinct subpopulations with different functions, the classically (M1) and the alternatively (M2) activated macrophages, have been found in these tissues. Reciprocal skewing of macrophage polarization between the M1 and M2 states is a process modulated by diet, humoral and transcription factors, such as the nuclear receptor peroxisome proliferator-activated receptor gamma. SUMMARY: Recent literature highlights the importance not only of the number of infiltrated macrophages, but also their activation in the maintenance of the inflammation state. Identifying mechanisms and molecules able to modify the balance between M1 and M2 represents a promising field of research

Rôle du récepteur nucléaire PPARg dans les macrophages alternatifs humains (de l'inflammation à l'homéostasie du cholestérol)

Une des étapes cruciales de la formation des plaques d'athérosclérose est représentée par l'infiltration des monocytes dans l'intima artériel où ils se différencient en macrophages et participent à la mise en place d'un environnement pro-inflammatoire au sein des lésions. De récentes études font état du caractère versatile des macrophages, leur permettant d'adapter la réponse inflammatoire à l'environnement. En effet, les cytokines de type Th1 induisent le phénotype d'activation classique des macrophages qui favorise la production des molécules pro-inflammatoires. En revanche, les cytokines de type Th2 induisent une activation alternative des macrophages qui leur confère des propriétés anti-inflammatoires. Nos résultats montrent, pour la première fois, la présence des macrophages alternatifs au sein des lésions d'athérosclérose humaines. Nous avons également mis en évidence une corrélation entre l'expression génique des marqueurs de macrophages alternatifs (tel que le récepteur du mannose MR ) et du récepteur nucléaire PPARg au sein même des lésions. PPARg est un récepteur nucléaire qui exerce des fonctions anti-inflammatoires et régule l'homéostasie du cholestérol des macrophages. Nous avons observé in vitro que l'activation de PPARg par les glitazones accroît le caractère anti-inflammatoire des macrophages alternatifs. De plus, chez des patients traités pendant 2 mois avec de la pioglitazone, une des glitazones couramment utilisée en clinique, les monocytes et lymphocytes circulants expriment d'avantage le marqueur de la différenciation alternative des macrophages, MR. D'autre part, nous avons observé que l'activité de l'enzyme 11beta-HSD1, responsable de la conversion de la cortisone cellulaire en corticol, est élevée et inductible par les glitazones uniquement dans les macrophages alternatifs. Nous avons également étudié le métabolisme du cholestérol dans ces macrophages et observé une nette augmentation de la captation du cholestérol et une diminution de son efflux dans les macrophages alternatifs. Ce travail contribue à une meilleure connaissance des composants de la plaque d'athérome et décrit les glitazones comme des activateurs potentiels des fonctions anti-inflammatoires des macrophages alternatifs, ce qui ouvre la voie à de nouvelles approches thérapeutiques de l'athérosclérose.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages.

International audienceAdipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR)γ are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPARγ target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD(+) concentration was observed. Interestingly, LXR activation decreased the PPARγ-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPARγ pathways in human macrophages