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New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded protein response. In this article, we review how targeting these inter‐related processes may provide novel treatment targets and new therapeutic strategies for reducing MI size, preventing the onset of HF following AMI.

There remains an unmet need to identify novel therapeutic strategies capable of protecting the myocardium against the detrimental effects of acute ischemia–reperfusion injury (IRI), to reduce myocardial infarct (MI) size and prevent the onset of heart failure (HF) following acute myocardial infarction (AMI). In this regard, perturbations in mitochondrial morphology with an imbalance in mitochondrial fusion and fission can disrupt mitochondrial metabolism, calcium homeostasis, and reactive oxygen species production, factors which are all known to be critical determinants of cardiomyocyte death following acute myocardial IRI. As such, therapeutic approaches directed at preserving the morphology and functionality of mitochondria may provide an important strategy for cardioprotection. In this article, we provide an overview of the alterations in mitochondrial morphology which occur in response to acute myocardial IRI, and highlight the emerging therapeutic strategies for targeting mitochondrial shape to preserve mitochondrial function which have the future therapeutic potential to improve health outcomes in patients presenting with AMI.

Anthracycline‐induced cardiotoxicity remains a major limitation in cancer therapy, affecting long‐term cardiovascular health in survivors. Dietary nitrate supplementation has shown cardioprotective effects in preclinical models of doxorubicin (Dox)‐induced and ischemia–reperfusion injury, but it is unclear whether nitrate and/or nitrite (NOx) would have adverse effects on the anticancer efficacy of the drug. To evaluate Dox efficacy against triple‐negative breast cancer (TNBC) in the presence of dietary nitrate and nitrite, tumor‐bearing BALB/c mice ( N = 5 mice per group, 10 mice total) were treated with four weekly intravenous doses of Dox with or without NOx supplementation of their drinking water. Cardiac tissue from the NOx‐treated mice exhibited less fibrosis and lower levels of 4‐hydroxynonenal‐modified proteins, a marker of lipid oxidation and oxidative stress. Tumor sizes varied, but most regressed by the final Dox dose. Importantly, NOx supplementation did not compromise the antitumor efficacy of Dox nor did it promote pulmonary metastasis; instead, a trend toward fewer metastatic lesions was observed. These findings support the potential clinical use of dietary nitrate and nitrite as adjuncts to Dox treatment to mitigate cardiotoxicity without impairing anticancer outcomes.

IntroductionThe benefits of non-selective ROCK1/2 inhibitors in cardioprotection are well-known, especially in the treatment of hypertension and vasospastic angina. Fasudil, (a commonly used ROCK1/2 inhibitor) reduces infarct size and no re-flow following ischaemia/reperfusion, however it induces hypotension, which is undesirable during acute myocardial infarction (MI). ROCK inhibitors are novel agents, as they induce vasodilation by acting directly on vascular smooth muscle cells (VSMC), and myosin light chain phosphatase (MLCP), to prevent phosphorylation of myosin light chain kinase (MLC2). This is beneficial during lethal reperfusion injury when an increase in coronary vascular tone may contribute towards microvascular damage and obstruction (MVO). The ideal ROCKi for coronary circulation protection, would be a potent vasodilator, but would not compromise blood pressure or myocardial contractility.AimsWe investigated i) The vasodilatory properties of Chroman 1 (Ch1) (a selective ROCK 2 inhibitor), relative to Fasudil, to ascertain whether this agent could demonstrate effective vasorelaxation and ii) Performed a dose response experiment using a rat model in-vivo, to test the effects of Ch1 on myocardial contractility and left ventricular ejection fraction (LVEF%), mean arterial pressure (MAP) and heart rate.MethodsThoracic aorta of male SD rats was dissected and 3mm segments were suspended into a tissue bath. These vascular rings were pre-constricted with 1µM PE and treated with [10-12]-[10-5]mM Ch1, or [10-9]-[10-5]mM Fasudil, or DMSO control. Separately, male SD rats were anaesthetised with isoflurane, intubated and ventilated. LVEF% was measured in-vivo using echocardiography in a closed chest rat model, following the addition of Ch1 (30-300µg/kg) administered i.p, at 15-minute intervals. Blood pressure and heart rate were recorded at baseline and throughout.ResultsCh1 is a potent vasodilator of aortic rings compared to Fasudil, (EC50 Ch1 9.6x10-8 vs EC50 Fasudil 9.0 x10-6) , and to DMSO control, (n=6) (figure 1). In-vivo, echocardiography demonstrated no significant difference in baseline LVEF% between groups, (Ch1 81.4% vs vehicle 82.6%, p>0.05, n=5) nor after cumulative addition of Ch1 (Ch1 76.6% vs vehicle 81.0 %, p=0.97, n=5). At doses of 300µg/kg, mean arterial pressure (MAP) was reduced in the Ch1 treatment group, (76 vs 92mmHg, p=0.02, n=5) however, average MAP did not fall below 70mmHg and normalised by the end of the period. There were no significant differences in mean HR (BPM) between groups.Abstract BS55 Figure 1Dose dependent relaxation of aortic rings by Ch1, Fasudil. * Ch1 vs control, #Ch1 vs Fasudil. **p<0.01, ***p<0.0001. #p<0.05, ##p<0.01, ###p<0.0001ConclusionROCK2 inhibition is associated with significant VSMC relaxation, but not a reduction in LVEF% or myocardial contractility. This suggests that the contractile effects of ROCK2 are vascular specific. Ch1 may be a suitable drug for further studies of I/R and MVO.Conflict of Interestn/a

Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in humans—in animals, STAT3 is causally involved in cardioprotection. In response to late ischemic conditioning, canonical function of STAT3 activation upregulates the expression of cardioprotective and anti-apoptotic proteins. In its non-canonical function, STAT3 is activated during ischemic conditioning and is part of the cardioprotective cytosolic survival activating factor enhancement pathway. Activated STAT3 is imported and localized to the mitochondria. Mitochondrial STAT3 stimulates the activity of mitochondrial electron transport chain complex I, reduces mitochondrial reactive oxygen species production and mitochondrial permeability transition pore opening. Finally, two novel aspects of STAT activation in cardioprotection are discussed: a genetic variance of the STAT encoding region as a potential primordial confounding variable for cardioprotection, and the cardioprotective potential of sodium–glucose cotransporter 2 inhibitors through STAT3 activation.

Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2S play also a role in endogenous cardioprotection, as in the case of ischaemic pre‐conditioning, so that preventing their increase might hamper self‐defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury.

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.

Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

BackgroundMyocardial infarction remains one of the main causes of death worldwide, despite undeniable progress in reperfusion strategies. Unfortunately, these do not reverse the molecular damage that has already occurred. Targeting cardiomyocyte loss following ischaemia-reperfusion injury (IRI) is an important therapeutic target, as infarct size predicts the risk of heart failure and one-year all-cause mortality. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are gaining wide acceptance as a predictive platform for cardiac drug testing and disease modelling; however, their functional immaturity is considered a major limitation. Here, paracrine protection mediated by cardiac mesenchymal stromal cells (cMSC) was tested in a novel in vitro platform using metabolically mature hiPSC-CMs and hypoxia-reoxygenation.MethodsA novel culture protocol by Feyen et al. was applied to obtain metabolically mature hiPSC-CMs. Its efficacy was determined by analysing cell purity with immunofluorescence and quantifying the expression of cardiomyocyte markers alongside structural and metabolic genes by single cell qRT-PCR. Mitochondrial function was assessed using the Seahorse XFe96 Analyzer. Time-course experiments were carried out to analyse cell death, in the presence and absence of cMSC conditioned media, through Draq7 uptake, in response to 0.1% O2 treatment and culture media modifications, followed by reoxygenation.ResultshiPSC-CMs with greater degree of maturity were obtained, as confirmed by upregulation of structural and metabolic genes. An increase in spare respiratory capacity and maximal respiration, in comparison to cells cultured in standard medium, suggested improved mitochondrial function. A significant increase in cell death of the mature hiPSC-CMs was observed in response to hypoxia in combination with nutrient deprivation, when compared to standard hiPSC-CMs. Moreover, 2h of hypoxia followed by 6h of reoxygenation, mimicking reperfusion injury, resulted in even greater extent of cell death of the mature CMs. Finally, cMSC conditioned medium added at the time of reoxygenation significantly reduced the proportion of mature hiPSC-CMs undergoing cell death.ConclusionsA novel in vitro model of ischaemia-reperfusion injury was developed using metabolically mature hiPSC-CMs and hypoxia-reoxygenation. The model was successfully employed as a platform for testing paracrine cardioprotection, however further studies are required to determine the molecular mechanism underlying cMSC secretome-mediated effects. This platform provides a more accurate humanised model to study the mechanisms of IRI and screen the safety and efficacy of novel cardioprotective agents.Conflict of InterestNA