Mikhail Kilin

Chronic continuous hypoxia (CCH) demonstrates a pronounced protective effect in cardiac ischemia-reperfusion (IR). Opioids and opioid receptors play a significant role in this process. It has been previously shown that metabolic syndrome (MS) impairs the development of adaptive myocardial resistance to IR. The aim of this study is to identify the relationship between the cardioprotective effect of CCH and opioid peptides in circulating blood and myocardial tissue, as well as the expression of opioid receptors in the myocardium of rats with and without MS. All rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). Some rats received high carbohydrate high fat diet for 90 days (MS) before IR. Some animals were exposed to CCH (21 days, 12% O₂) before IR. The plasma endomorphin-2, and dynorphin A levels were increased after CCH. Endomorphin-2, β-endorphin, dynorphin A (1–13), and met-enkephalin content in myocardial tissue was increased in response to CCH. In rats with MS, an increase in the plasma and myocardial opioid levels in response to CCH was reduced. A correlation was identified between plasma and myocardial tissue opioid peptide levels and the extent of myocardial injury, as well as between myocardial opioid peptide content and contractility. Furthermore, CCH and MS caused a reduction in the expression of δ- (DOR) and κ- (KOR) opioid receptors, and also an increase in µ- (MOR) opioid receptor expression. These findings suggest that a decrease in opioid peptide content could impair adaptive cardioprotection in MS. Graphical abstract

Highlights Diet-induced metabolic syndrome does not lead to mitochondrial respiration impairment and worsening of contractile dysfunction of the rat myocardium. Preservation of contractile function may be associated with substrate oxidation by complex II of the mitochondrial respiratory chain. It can be assumed that the initial metabolic changes of donors are not a significant obstacle to myocardial transplantation. AbstractBackground. Tissue resistance to acute ischemia is an important problem of medical science in general and transplantology in particular. At the same time, carbohydrate and lipid metabolism disorders can cause a decrease in organ resistance to ischemia, and the high prevalence of such disorders in the population is an important problem for the preservation of the transplanted organ.Aim. To assess the effect of experimental metabolic syndrome (MS) on the severity of myocardial contractile dysfunction during reperfusion, and the relationship between myocardial contractility in MS and mitochondrial respiration.Methods. The study was performed on Wistar rats. Metabolic syndrome (MS) was modeled by feeding rats of a high-carbohydrate, high-fat diet for 12 weeks. Post-ischemic myocardial contractility was assessed using an in vivo model of acute coronary occlusion-reperfusion (ACR) echocardiography and an isolated heart ischemia-reperfusion model. Mitochondria were isolated by differential centrifugation from the ischemic zone after ACR. Mitochondrial respiration was assessed in the presence of malate, pyruvate, and succinate.Results. Keeping rats on a diet for 12 weeks led to the formation of obesity, hypertension, increased blood glucose, triglyceride, leptin, and adiponectin levels, i.e., to the metabolic syndrome formation. Myocardial contraction parameters before ischemia modeling both in vivo and in the isolated heart model did not differ. Mitochondria of rats with MS were distinguished by greater efficiency of ADP/O respiration on both NAD+ and FAD+-dependent substrates.ACR in vivo led to a decrease in the contractile and pumping function of the myocardium, suppression of mitochondrial respiration equally in the group of control animals and animals with MS. Similar data were obtained in the isolated heart model. An inverse correlation link was established between the efficiency of mitochondrial respiration in rats with MS in the presence of a FAD+-dependent substrate and the value of the end-systolic volume at late stages of reperfusion. Such a relationship was not observed in the control group rats.Conclusion. The obtained results suggest that diet-induced MS does not lead to mitochondrial respiration impairment and aggravation of myocardial contractile dysfunction. Preservation of contractile function may be associated with oxidation of substrates by complex II of the mitochondrial respiratory chain. It can be assumed that the initial metabolic changes in donors are not a significant obstacle to myocardial transplantation.

Stress-induced cardiac injury (SICI) was modeled on female Wistar rats using a 24-h immobilization. SICI was quantified by ^99mTc-pyrophosphate accumulation in the myocardium. Blockade of β₁- and β₂-adrenergic receptors (AR) led to a decrease in SICI. β₁-AR antagonists nebivolol and atenolol almost completely prevented SICI. The selective β₂-AR antagonist ICI 118,551 increased SICI, while the selective β₃-AR antagonist L-748337 did not affect heart damage. The selective β₂-AR agonist formoterol increased cardiac tolerance to stress. These findings suggest that β₁-AR play a key role in the pathogenesis of SICI. Stimulation of β₂-AR enhances cardiac tolerance to stress. β₃-AR are not involved in the pathogenesis of SICI.

Background. The high mortality rate among patients with acute myocardial infarction (AMI) is an important problem of modern cardiology. In recent years, there has not been a significant decrease in mortality in AMI. Drugs used to treat AMI are not effective enough, so there is a need to develop fundamentally new drugs that can significantly increase the heart’s tolerance to ischemia/reperfusion (I/R). Angiotensin 1-7 peptide, which can increase cardiac tolerance to I/R by activating Mas receptor in myocardial tissue, could become a prototype of such drugs. The following enzymes are involved in the formation of the cardioprotective effect of angiotensin 1-7: NO-synthase, soluble guanylyl cyclase, phosphoinositide 3-kinase, extracellular signal-regulated kinases-1/2, Akt kinase and, possibly, protein kinase G. Indirect data indicate that the hypothetical end effector in the cardioprotective impact of angiotensin 1-7 could be mitochondrial or sarcolemmal ATP-sensitive K+ channel.Aim: To review 1-7 role in increasing the heart resistance to ischemia and reperfusion. The literature search was carried out in the PubMed database with queries “angiotensin 1-7 receptors”, “stress”, “angiotensin 1-7”, “mas receptor”, “cardioprotective effects of angiotensin 1-7”.

Background. It is known that the protective effect of adaptation and conditioning influence is weakened in animals with metabolic syndrome. Metabolic syndrome may be the basis for the failure of cardioprotection in clinical settings.The aim of the study. To identify the relationship between disorder in carbohydrate and lipid metabolism and a decrease in the effectiveness of the infarct-limiting effect of moderate chronic normobaric hypoxia; to check the possibility of correcting reduced cardioprotection by normalizing carbohydrate and lipid metabolism.Methods. The study included 64 Wistar rats. Metabolic syndrome was induced by feeding animals a high-carbohydrate, high-fat diet for 84 days. Chronic normobaric hypoxia was carried out for 21 days in the following mode: 12 % O2 : 0.3 % CO2. Metformin at a dose of 200 mg/kg/day or PPARα agonist WY14643 at a dose of 1 mg/kg/day were added to the drinking water of rats with metabolic syndrome during adaptation period to hypoxia. A 45-minute coronary occlusion and 120-minute reperfusion were performed, and the infarct size was determined. Indicators of lipid and carbohydrate metabolism, leptin, and adiponectin were studied in the blood serum.Results. The infarct-limiting effect of chronic normobaric hypoxia was weakened in animals with metabolic syndrome. Infarct size showed a direct correlation with decreased glucose tolerance and serum triglyceride levels. Using metformin therapy did not lead to the restoration of the infarct-limiting effect of chronic normobaric hypoxia, while the normalization of lipid metabolism with the use of the PPARα agonist WY14643 corrected the impairment of adaptive cardioprotection in rats with metabolic syndrome.Conclusion. The lack of cardioprotection at chronic normobaric hypoxia in rats with metabolic syndrome is associated with impaired carbohydrate and lipid metabolism. The PPARα agonist restores impaired lipid metabolism and adaptive cardioprotection.

Ischemic-reperfusion injuries of organs underlie such common pathologies as ischemic stroke and myocardial infarction and are the cause of death and disability in the population. In addition, ischemic lung damage is observed in pulmonary embolism. Advances in transplantology, as well as the widespread use of coronary artery bypass grafting, raise the problem of ischemia and reperfusion of organs during these manipulations. Progress made over the past three decades in the treatment of stroke and acute myocardial infarction (AMI) has slowed in recent years. Since patients with stroke and AMI are admitted to the hospital with ischemic damage to the brain or heart, it is no longer possible to influence its formation. However, it is possible to affect reperfusion injury to organs. Significant progress in improving the efficiency of kidney transplantation, in the treatment of stroke, pulmonary embolism and AMI can be achieved through the development of new drugs that can effectively prevent reperfusion damage of organs. Synthetic analogues of apelin with a long half-life can become prototypes of drugs with similar action. It has been found that apelins can increase the tolerance of the heart, brain, kidneys and lungs to ischemia/reperfusion (I/R). Apelins inhibit apoptosis and activate cardiomyocyte autophagy. The neuroprotective, cardioprotective, renoprotective, and pulmonoprotective effects of apelins are realized through intracellular signaling, including protein kinases, a mitochondrial variable permeability pore, and ATP-sensitive K+ channels. Enzyme-resistant analogues of apelin are promising peptides for the treatment of AMI, stroke, and I/R damage to the lungs, and kidneys.

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-3β 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.

An analysis of published data and the results of our own studies showed that activation of peripheral δ₂-opioid receptor (δ₂-OR) increases cardiac tolerance to reperfusion. It has been established that this δ₂-OR is localized in cardiomyocytes. Endogenous opioids are not involved in the regulation of cardiac resistance to reperfusion in non-adapted rats. The infarct-limiting effect of δ₂-OR agonist deltorphin II depends on the activation of following protein kinases: PKCδ, ERK1/2, PI3K, PCG. SarcK_ATP channel and MPT pore are hypothetical end effectors of the cardioprotective effect of deltorphin II.

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 K_ATP channels and the MPT pore.

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-3β, 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 mitoK_ATP 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.