Discovery of new therapeutic redox targets for cardioprotection against ischemia/reperfusion injury and heart failure

Global epidemiological studies reported a shift from maternal/infectious communicable diseases to chronic non-communicable diseases and a major part is attributable to atherosclerosis and metabolic disorders. Accordingly, ischemic heart disease was identified as a leading risk factor for global mortality and morbidity with a prevalence of 128 million people. Almost 9 million premature deaths can be attributed to ischemic heart disease and subsequent acute myocardial infarction and heart failure, also representing a substantial socioeconomic burden. As evidenced by typical oxidative stress markers such as lipid peroxidation products or oxidized DNA/RNA bases, the formation of reactive oxygen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial resperatory chain) plays a central role for the severity of ischemia/reperfusion damage. The underlying mechanisms comprise direct oxidative damage but also adverse redox-regulation of kinase and calcium signaling, inflammation and cardiac remodeling among others. These processes and the role of reactive oxygen species are discussed in the present review. We also present and discuss potential targets for redox-based therapies that are either already established in the clinics (e.g. guanylyl cyclase activators and stimulators) or at least successfully tested in preclinical models of myocardial infarction and heart failure (mitochondria-targeted antioxidants). However, reactive oxygen species have not only detrimental effects but are also involved in essential cellular signaling and may even act protective as seen by ischemic pre- and post-conditioning or eustress – which makes redox therapy quite challenging

The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies

IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria : guidelines of the EU-CARDIOPROTECTION COST Action

Full list of the EU-CARDIOPROTECTION COST Action CA16225 Working group members is provided at the end of the article in Acknowledgements section. Funding Information: This article is based on the work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). DJH is supported by the Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006). SL is supported by grants from the South African Department of Science and Technology and the South African National Research Foundation. SMD is supported by grants from the British Heart Foundation (PG/19/51/34493 and PG/16/85/32471). GH is supported by the German Research Foundation (SFB 1116 B8). MRM is supported by the Spanish Institute of Health Carlos III (FIS PI19/01196 and CIBER-CV). RS is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. PF is supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program—TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University. Funding Information: The IMPACT criteria were presented for approval to the Management Committee of the EU-CARDIOPROTECTION COST Action CA16225: Pavle Adamovski, Ioanna Andreadou, Saime Batirel, Monika Bartekov?, Luc Bertrand, Christophe Beauloye, David Biedermann, Vilmante Borutaite, Hans Erik Botker, Stefan Chlopicki, Maija Dambrova, Sean Davidson, Yvan Devaux, Fabio Di Lisa, Dragan Djuric, David Erlinge, Ines Falcao-Pires, P?ter Ferdinandy, Eleftheria Galatou, Alfonso Garcia-Sosa, Henrique Girao, Zoltan Giricz, Mariann Gyongyosi, Derek J Hausenloy, Donagh Healy, Gerd Heusch, Vladimir Jakovljevic, Jelena Jovanic, George Kararigas, Risto Kerkal, Frantisek Kolar, Brenda Kwak, Przemys?aw Leszek, Edgars Liepinsh , Jacob Lonborg, Sarah Longnus, Jasna Marinovic, Danina Mirela Muntean, Lana Nezic, Michel Ovize, Pasquale Pagliaro, Clarissa Pedrosa Da Costa Gomes, John Pernow, Andreas Persidis, S?ren Erik Pischke, Bruno Podesser, Ines Poto?njak, Fabrice Prunier, Tanya Ravingerova, Marisol Ruiz-Meana, Alina Serban, Katrine Slagsvold, Rainer Schulz, Niels van Royen, Belma Turan, Marko Vendelin, Stewart Walsh, Nace Zidar, Coert Zuurbier, Derek Yellon. Publisher Copyright: © 2021, The Author(s).Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.publishersversionPeer reviewe

Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study

Aims: Remote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. Methods and results: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p  15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. Conclusion: RIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling

Acute administration of the olive constituent, oleuropein, combined with ischemic postconditioning increases myocardial protection by modulating oxidative defense

Oleuropein, one of the main polyphenolic constituents of olive, is cardioprotective against ischemia reperfusion injury (IRI). We aimed to assess the cardioprotection afforded by acute administration of oleuropein and to evaluate the underlying mechanism. Importantly, since antioxidant therapies have yielded inconclusive results in attenuating IRI-induced damage on top of conditioning strategies, we investigated whether oleuropein could enhance or imbed the cardioprotective manifestation of ischemic postconditioning (PostC). Oleuropein, given during ischemia as a single intravenous bolus dose reduced the infarct size compared to the control group both in rabbits and mice subjected to myocardial IRI. None of the inhibitors of the cardioprotective pathways, l-NAME, wortmannin and AG490, influence its infarct size limiting effects. Combined oleuropein and PostC cause further limitation of infarct size in comparison with PostC alone in both animal models. Oleuropein did not inhibit the calcium induced mitochondrial permeability transition pore opening in isolated mitochondria and did not increase cGMP production. To provide further insights to the different cardioprotective mechanism of oleuropein, we sought to characterize its anti-inflammatory potential in vivo. Oleuropein, PostC and their combination reduce inflammatory monocytes infiltration into the heart and the circulating monocyte cell population. Oleuropein's mechanism of action involves a direct protective effect on cardiomyocytes since it significantly increased their viability following simulated IRI as compared to non-treated cells. Οleuropein confers additive cardioprotection on top of PostC, via increasing the expression of the transcription factor Nrf-2 and its downstream targets in vivo. In conclusion, acute oleuropein administration during ischemia in combination with PostC provides robust and synergistic cardioprotection in experimental models of IRI by inducing antioxidant defense genes through Nrf-2 axis and independently of the classic cardioprotective signaling pathways (RISK, cGMP/PKG, SAFE)

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal

Protection by the NO-Donor SNAP and BNP against Hypoxia/Reoxygenation in Rat Engineered Heart Tissue

In vitro assays could replace animal experiments in drug screening and disease modeling, but have shortcomings in terms of functional readout. Force-generating engineered heart tissues (EHT) provide simple automated measurements of contractile function. Here we evaluated the response of EHTs to hypoxia/reoxygenation (H/R) and the effect of known cardiocytoprotective molecules. EHTs from neonatal rat heart cells were incubated for 24 h in EHT medium. Then they were subjected to 180 min hypoxia (93% N2, 7% CO2) and 120 min reoxygenation (40% O2, 53% N2, 7% CO2), change of medium and additional follow-up of 48 h. Time-matched controls (40% O2, 53% N2, 7% CO2) were run for comparison. The following conditions were applied during H/R: fresh EHT medium (positive control), the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 10-7, 10-6, 10-5 M) or the guanylate cyclase activator brain type natriuretic peptide (BNP, 10-9, 10-8, 10-7 M). Frequency and force of contraction were repeatedly monitored over the entire experiment, pH, troponin I (cTnI), lactate dehydrogenase (LDH) and glucose concentrations measured in EHT medium. Beating activity of EHTs in 24 h-medium ceased during hypoxia, partially recovered during reoxygenation and reached time-control values during follow-up. H/R was accompanied by a small increase in LDH and non-significant increase in cTnI. In fresh medium, some EHTs continued beating during hypoxia and all EHTs recovered faster during reoxygenation. SNAP and BNP showed small but significant protective effects during reoxygenation. EHTs are applicable to test potential cardioprotective compounds in vitro, monitoring functional and biochemical endpoints, which otherwise could be only measured by using in vivo or ex vivo heart preparations. The sensitivity of the model needs improvement