Effect of Cold Adaptation on the State of Cardiovascular System and Cardiac Tolerance to Ischemia/Reperfusion Injury.

Despite the unconditional success achieved in the treatment and prevention of AMI over the past 40 years, mortality in this disease remains high. Hence, it is necessary to develop novel drugs with mechanism of action different from those currently used in clinical practices. Studying the molecular mechanisms involved in the cardioprotective effect of adapting to cold could contribute to the development of drugs that increase cardiac tolerance to the impact of ischemia/reperfusion. An analysis of the published data shows that the long-term human stay in the Far North contributes to the occurrence of cardiovascular diseases. At the same time, chronic and continuous exposure to cold increases tolerance of the rat heart to ischemia/ reperfusion. It has been demonstrated that the cardioprotective effect of cold adaptation depends on the activation of ROS production, stimulation of the ß2-adrenergic receptor and protein kinase C, MPT pore closing, and KATP channel.

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists.

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1ß, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3ß, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

Do platelets protect the heart against ischemia/reperfusion injury or exacerbate cardiac ischemia/reperfusion injury? The role of PDGF, VEGF, and PAF.

BACKGROUND: Acute myocardial infarction (AMI) is one of the main causes of death. It is quite obvious that there is an urgent need to develop new approaches for treatment of AMI. OBJECTIVE: This review analyzes data on the role of platelets in the regulation of cardiac tolerance to ischemia/reperfusion (I/R). METHODS: It was performed a search of topical articles using PubMed databases. FINDINGS: Platelets activated by a cholesterol-enriched diet, thrombin, and myocardial ischemia exacerbate I/R injury of the heart. The P2Y12 receptor antagonists, remote ischemic postconditioning and conditioning alter the properties of platelets. Platelets acquire the ability to increase cardiac tolerance to I/R. Platelet-derived growth factors (PDGFs) increase tolerance of cardiomyocytes and endothelial cells to I/R. PDGF receptors (PDGFRs) were found in cardiomyocytes and endothelial cells. PDGFs decrease infarct size and partially abrogate adverse postinfarction remodeling. Protein kinase C, phosphoinositide 3-kinase, and Akt involved in the cytoprotective effect of PDGFs. Vascular endothelial growth factor increased cardiac tolerance to I/R and alleviated adverse postinfarction remodeling. The platelet-activating factor (PAF) receptor inhibitors increase cardiac tolerance to I/R in vivo. PAF enhances cardiac tolerance to I/R in vitro. It is possible that PAF receptor inhibitors could protect the heart by blocking PAF receptor localized outside the heart. PAF protects the heart through activation of PAF receptor localized in cardiomyocytes or endothelial cells. Reactive oxygen species and kinases are involved in the cardioprotective effect of PAF. CONCLUSION: Platelets play an important role in the regulation of cardiac tolerance to I/R.

Potential Mechanisms for Organoprotective Effects of Exogenous Nitric Oxide in an Experimental Study.

Performing cardiac surgery under cardiopulmonary bypass (CPB) and circulatory arrest (CA) provokes the development of complications caused by tissue metabolism, microcirculatory disorders, and endogenous nitric oxide (NO) deficiency. This study aimed to investigate the potential mechanisms for systemic organoprotective effects of exogenous NO during CPB and CA based on the assessment of dynamic changes in glycocalyx degradation markers, deformation properties of erythrocytes, and tissue metabolism in the experiment. A single-center prospective randomized controlled study was conducted on sheep, n = 24, comprising four groups of six in each. In two groups, NO was delivered at a dose of 80 ppm during CPB ("CPB + NO" group) or CPB and CA ("CPB + CA + NO"). In the "CPB" and "CPB + CA" groups, NO supply was not carried out. NO therapy prevented the deterioration of erythrocyte deformability. It was associated with improved tissue metabolism, lower lactate levels, and higher ATP levels in myocardial and lung tissues. The degree of glycocalyx degradation and endothelial dysfunction, assessed by the concentration of heparan sulfate proteoglycan and asymmetric dimethylarginine, did not change when exogenous NO was supplied. Intraoperative delivery of NO provides systemic organoprotection, which results in reducing the damaging effects of CPB on erythrocyte deformability and maintaining normal functioning of tissue metabolism.

Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart-The signaling mechanism.

BACKGROUND: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1-7 has some promise in this regard. OBJECTIVE: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1-7. METHODS: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS: Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1-7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1-7. Angiotensin 1-7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1-7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1-7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1-7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1-7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1-7. However, the specific end-effector of the cardioprotective impact of angiotensin 1-7 remains unknown. CONCLUSION: The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1-7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal KATP channel or the mitochondrial KATP channel.

The role of ß-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do ß-adrenergic receptor agonists and antagonists protect the heart?

BACKGROUND: Catecholamines and ß-adrenergic receptors (ß-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of ß-AR ligands. METHODS: We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of ß-AR agonists and antagonists. RESULTS: The infarct-reducing effect of ß-AR antagonists did not depend on a decrease in the heart rate. The target for ß-blockers is not only cardiomyocytes but also neutrophils. ß1-blockers (metoprolol, propranolol, timolol) and the selective ß2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of ß1- and ß2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All ß-AR ligands that reduced infarct size are the selective or nonselective ß1-blockers. It was hypothesized that ß1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of ß1-AR, ß2-AR, and ß3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of ß-AR agonists is mediated via the activation of kinases and reactive oxygen species production. CONCLUSIONS: It is unclear why ß-blockers with the similar receptor selectivity have the infarct-sparing effect while other ß-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of ß-blockers in reperfusion? Why did in early studies ß-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies ß-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective ß-AR ligands depends on the answers to these questions.

Ferroptosis, a Regulated Form of Cell Death, as a Target for the Development of Novel Drugs Preventing Ischemia/Reperfusion of Cardiac Injury, Cardiomyopathy and Stress-Induced Cardiac Injury.

The hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is about 6% and has not decreased in recent years. The leading cause of death of these patients is ischemia/reperfusion (I/R) cardiac injury. It is quite obvious that there is an urgent need to create new drugs for the treatment of STEMI based on knowledge about the pathogenesis of I/R cardiac injury, in particular, based on knowledge about the molecular mechanism of ferroptosis. In this study, it was demonstrated that ferroptosis is involved in the development of I/R cardiac injury, antitumor drug-induced cardiomyopathy, diabetic cardiomyopathy, septic cardiomyopathy, and inflammation. There is indirect evidence that ferroptosis participates in stress-induced cardiac injury. The activation of AMPK, PKC, ERK1/2, PI3K, and Akt prevents myocardial ferroptosis. The inhibition of HO-1 alleviates myocardial ferroptosis. The roles of GSK-3ß and NOS in the regulation of ferroptosis require further study. The stimulation of Nrf2, STAT3 prevents ferroptosis. The activation of TLR4 and NF-κB promotes ferroptosis of cardiomyocytes. MiR-450b-5p and miR-210-3p can increase the tolerance of cardiomyocytes to hypoxia/reoxygenation through the inhibition of ferroptosis. Circ_0091761 RNA, miR-214-3p, miR-199a-5p, miR-208a/b, miR-375-3p, miR-26b-5p and miR-15a-5p can aggravate myocardial ferroptosis.

δ-Opioid Receptor as a Molecular Target for Increasing Cardiac Resistance to Reperfusion in Drug Development.

An analysis of published data and the results of our own studies reveal that the activation of a peripheral δ2-opioid receptor (δ2-OR) increases the cardiac tolerance to reperfusion. It has been found that this δ2-OR is localized in cardiomyocytes. Endogenous opioids are not involved in the regulation of cardiac resistance to reperfusion. The infarct-limiting effect of the δ2-OR agonist deltorphin II depends on the activation of several protein kinases, including PKCδ, ERK1/2, PI3K, and PKG. Hypothetical end-effectors of the cardioprotective effect of deltorphin II are the sarcolemmal KATP channels and the MPT pore.

Do reactive oxygen species damage or protect the heart in ischemia and reperfusion? Analysis on experimental and clinical data.

The role of reactive oxygen species (ROS) in ischemic and reperfusion (I/R) injury of the heart has been discussed for more than 40 years. It has been demonstrated that reperfusion triggers a multiple increase in free radical generation in the isolated heart. Antioxidants were found to have the ability to mitigate I/R injury of the heart. However, it is unclear whether their cardioprotective effect truly depends on the decrease of ROS levels in myocardial tissues. Since high doses and high concentrations of antioxidants were experimentally used, it is highly likely that the cardioprotective effect of antioxidants depends on their interaction not only with free radicals but also with other molecules. It has been demonstrated that the antioxidant N-2-mercaptopropionyl glycine or NDPH oxidase knockout abolished the cardioprotective effect of ischemic preconditioning. Consequently, there is evidence that ROS protect the heart against the I/R injury.

A historical literature review of coronary microvascular obstruction and intra-myocardial hemorrhage as functional/structural phenomena.

The analysis of experimental data demonstrates that platelets and neutrophils are involved in the no-reflow phenomenon, also known as microvascular obstruction (MVO). However, studies performed in the isolated perfused hearts subjected to ischemia/reperfusion (I/R) do not suggest the involvement of microembolization and microthrombi in this phenomenon. The intracoronary administration of alteplase has been found to have no effect on the occurrence of MVO in patients with acute myocardial infarction. Consequently, the major events preceding the appearance of MVO in coronary arteries are independent of microthrombi, platelets, and neutrophils. Endothelial cells appear to be the target where ischemia can disrupt the endothelium-dependent vasodilation of coronary arteries. However, reperfusion triggers more pronounced damage, possibly mediated by pyroptosis. MVO and intra-myocardial hemorrhage contribute to the adverse post-infarction myocardial remodeling. Therefore, pharmacological agents used to treat MVO should prevent endothelial injury and induce relaxation of smooth muscles. Ischemic conditioning protocols have been shown to prevent MVO, with L-type Ca 2+ channel blockers appearing the most effective in treating MVO.

The Signaling Mechanism of Remote Postconditioning of the Heart: Prospects of the Use of Remote Postconditioning for the Treatment of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) remains the leading cause of mortality in the world, highlighting an urgent need for the development of novel, more effective approaches for the treatment of AMI. Remote postconditioning (RPost) of the heart could be a useful approach. It was demonstrated that RPost triggers infarct size reduction, improves contractile function of the heart in reperfusion, mitigates apoptosis, and stimulates autophagy in animals with coronary artery occlusion and reperfusion. Endogenous opioid peptides and adenosine could be involved in RPost. It was found that kinases and NO-synthase participate in RPost. KATP channels, MPT pore, and STAT3 could be hypothetical end-effectors of RPost. Metabolic syndrome and old age abolish the cardioprotective effect of RPost in rats. The data on the efficacy of RPost in clinical practice are inconsistent. These data are discussed in the review.

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury.

BACKGROUND: The use of percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is associated with a mortality rate of 5%-7%. It is clear that there is an urgent need to develop new drugs that can effectively prevent cardiac reperfusion injury. ATP-sensitive K+ (KATP ) channel openers (KCOs) can be classified as such drugs. RESULTS: KCOs prevent irreversible ischemia and reperfusion injury of the heart. KATP channel opening promotes inhibition of apoptosis, necroptosis, pyroptosis, and stimulation of autophagy. KCOs prevent the development of cardiac adverse remodeling and improve cardiac contractility in reperfusion. KCOs exhibit antiarrhythmic properties and prevent the appearance of the no-reflow phenomenon in animals with coronary artery occlusion and reperfusion. Diabetes mellitus and a cholesterol-enriched diet abolish the cardioprotective effect of KCOs. Nicorandil, a KCO, attenuates major adverse cardiovascular event and the no-reflow phenomenon, reduces infarct size, and decreases the incidence of ventricular arrhythmias in patients with acute myocardial infarction. CONCLUSION: The cardioprotective effect of KCOs is mediated by the opening of mitochondrial KATP (mitoKATP ) and sarcolemmal KATP (sarcKATP ) channels, triggered free radicals' production, and kinase activation.

Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling.

In-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is 5-6%. Consequently, it is necessary to develop fundamentally novel drugs capable of reducing mortality in patients with acute myocardial infarction. Apelins could be the prototype for such drugs. Chronic administration of apelins mitigates adverse myocardial remodeling in animals with myocardial infarction or pressure overload. The cardioprotective effect of apelins is accompanied by blockage of the MPT pore, GSK-3ß, and the activation of PI3-kinase, Akt, ERK1/2, NO-synthase, superoxide dismutase, glutathione peroxidase, matrix metalloproteinase, the epidermal growth factor receptor, Src kinase, the mitoKATP channel, guanylyl cyclase, phospholipase C, protein kinase C, the Na+/H+ exchanger, and the Na+/Ca2+ exchanger. The cardioprotective effect of apelins is associated with the inhibition of apoptosis and ferroptosis. Apelins stimulate the autophagy of cardiomyocytes. Synthetic apelin analogues are prospective compounds for the development of novel cardioprotective drugs.

The Infarct-Reducing Effect of the δ2 Opioid Receptor Agonist Deltorphin II: The Molecular Mechanism.

The search for novel drugs for the treatment of acute myocardial infarction and reperfusion injury of the heart is an urgent aim of modern pharmacology. Opioid peptides could be such potential drugs in this area. However, the molecular mechanism of the infarct-limiting effect of opioids in reperfusion remains unexplored. The objective of this research was to study the signaling mechanisms of the cardioprotective effect of deltorphin II in reperfusion. Rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The ratio of infarct size/area at risk was determined. This study indicated that the cardioprotective effect of deltorphin II in reperfusion is mediated via the activation of peripheral δ2 opioid receptor (OR), which is most likely localized in cardiomyocytes. We studied the role of guanylyl cyclase, protein kinase Cδ (PKCδ), phosphatidylinositol-3-kinase (PI3-kinase), extracellular signal-regulated kinase-1/2 (ERK1/2-kinase), ATP-sensitive K+-channels (KATP channels), mitochondrial permeability transition pore (MPTP), NO synthase (NOS), protein kinase A (PKA), Janus 2 kinase, AMP-activated protein kinase (AMPK), the large conductance calcium-activated potassium channel (BKCa-channel), reactive oxygen species (ROS) in the cardioprotective effect of deltorphin II. The infarct-reducing effect of deltorphin II appeared to be mediated via the activation of PKCδ, PI3-kinase, ERK1/2-kinase, sarcolemmal KATP channel opening, and MPTP closing.

Regulation of autophagy of the heart in ischemia and reperfusion.

Ischemia/reperfusion (I/R) of the heart leads to increased autophagic flux. Preconditioning stimulates autophagic flux by AMPK and PI3-kinase activation and mTOR inhibition. The cardioprotective effect of postconditioning is associated with activation of autophagy and increased activity of NO-synthase and AMPK. Oxidative stress stimulates autophagy in the heart during I/R. Superoxide radicals generated by NADPH-oxidase acts as a trigger for autophagy, possibly due to AMPK activation. There is reason to believe that AMPK, GSK-3ß, PINK1, JNK, hexokinase II, MEK, PKCα, and ERK kinases stimulate autophagy, while mTOR, PKCδ, Akt, and PI3-kinase can inhibit autophagy in the heart during I/R. However, there is evidence that PI3-kinase could stimulate autophagy in ischemic preconditioning of the heart. It was found that transcription factors FoxO1, FoxO3, NF-κB, HIF-1α, TFEB, and Nrf-2 enhance autophagy in the heart in I/R. Transcriptional factors STAT1, STAT3, and p53 inhibit autophagy in I/R. MicroRNAs could stimulate and inhibit autophagy in the heart in I/R. Long noncoding RNAs regulate the viability and autophagy of cardiomyocytes in hypoxia/reoxygenation (H/R). Nitric oxide (NO) donors and endogenous NO could activate autophagy of cardiomyocytes. Activation of heme oxygenase-1 promotes cardiomyocyte tolerance to H/R and enhances autophagy. Hydrogen sulfide increases cardiac tolerance to I/R and inhibits apoptosis and autophagy via mTOR and PI3-kinase activation.

Pyroptosis is a drug target for prevention of adverse cardiac remodeling: The crosstalk between pyroptosis, apoptosis, and autophagy.

Acute myocardial infarction (AMI) is one of the main reasons of cardiovascular disease-related death. The introduction of percutaneous coronary intervention to clinical practice dramatically decreased the mortality rate in AMI. Adverse cardiac remodeling is a serious problem in cardiology. An increase in the effectiveness of AMI treatment and prevention of adverse cardiac remodeling is difficult to achieve without understanding the mechanisms of reperfusion cardiac injury and cardiac remodeling. Inhibition of pyroptosis prevents the development of postinfarction and pressure overload-induced cardiac remodeling, and mitigates cardiomyopathy induced by diabetes and metabolic syndrome. Therefore, it is reasonable to hypothesize that the pyroptosis inhibitors may find a role in clinical practice for treatment of AMI and prevention of cardiac remodeling, diabetes and metabolic syndrome-triggered cardiomyopathy. It was demonstrated that pyroptosis interacts closely with apoptosis and autophagy. Pyroptosis could be inhibited by nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 inhibitors, caspase-1 inhibitors, microRNA, angiotensin-converting enzyme inhibitors, angiotensin Ⅱ receptor blockers, and traditional Chinese herbal medicines.

Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season.

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

Pharmacological Approaches to Limit Ischemic and Reperfusion Injuries of the Heart: Analysis of Experimental and Clinical Data on P2Y12 Receptor Antagonists.

Ischemic and reperfusion injuries of the heart underlie the pathogenesis of acute myocardial infarction (AMI) and sudden cardiac death. The mortality rate is still high and is 5-7% in patients with ST-segment elevation myocardial infarction. The review is devoted to pharmacological approaches to limitation of ischemic and reperfusion injuries of the heart. The article analyzes experimental evidence and the clinical data on the effects of P2Y12 receptor antagonists on the heart's tolerance to ischemia/reperfusion in animals with coronary artery occlusion and reperfusion and also in patients with AMI. Chronic administration of ticagrelor prevented adverse remodeling of the heart. There is evidence that sphingosine-1-phosphate is the molecule that mediates the infarct-reducing effect of P2Y12 receptor antagonists. It was discussed a role of adenosine in the cardioprotective effect of ticagrelor.

The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury.

In the last 10 years, mortality from acute myocardial infarction (AMI) has not significantly decreased. This situation is associated with the absence in clinical practice of highly effective drugs capable of preventing the occurrence of reperfusion injury of the heart. Necroptosis inhibitors may become prototypes for the creation of highly effective drugs that increase cardiac tolerance to ischemic/reperfusion (I/R) and reduce the mortality rate in patients with AMI. Necroptosis is involved in I/R cardiac injury and inhibition of RIPK1 or RIPK3 contributes to an increase in cardiac tolerance to I/R. Necroptosis could also be involved in the development of adverse remodeling of the heart. It is unclear whether pre- and postconditioning could inhibit necroptosis of cardiomyocytes and endothelial cells. The role of necroptosis in coronary microvascular obstruction and the no-reflow phenomenon also needs to be studied. MicroRNAs and LncRNAs can regulate necroptotic cell death. Ca2+ overload and reactive oxygen species could be the triggers of necroptosis. Activation of kinases (p38, JNK1, Akt, and mTOR) could promote necroptotic cell death. The interaction of necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis is discussed. The water-soluble necroptosis inhibitors may be highly effective drugs for treatment of AMI or stroke. It is possible that microRNAs may become the basis for creating drugs for treatment of diseases triggered by I/R of organs.

Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms.

It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.