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

Abstract

BackgroundThe 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.ResultsKCOs 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.ConclusionThe 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.

Exploitation of KATP channels for cardiac surgery

“…Another myocyte study found that diazoxide was protective against apoptosis, although protection depended on the timing of treatment [130] . The cardioprotection associated with diazoxide in a swine model was found to result from decreased myocyte apoptosis and mitochondrial damage [131] . Recent reviews have also discussed the inhibition of apoptosis as a potential mechanism of K ATP channel modulation in cardioprotection [132] .…”

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

“…However, GLP-1(7-36) inhibits K ATP channels in β-cells of the islets of Langerhans, which leads to increased insulin secretion [122]. It should be noted that K ATP channels in cardiomyocytes and in β-cells are different [123]. Apparently, this feature of K ATP channels allows GLP-1 to block them in β-cells and activate them in cardiomyocytes.…”

“…In contrast, the activation of GSK-3β aggravates I/R injury of the heart [83]. K ATP channels, big conductance Ca 2+activated K + channels (BK Ca channels), and MPT pores are involved and are hypothetical end-effectors of ischemic pre-and postconditioning [18,83,123]. It has been found that K ATP channel opening, BK Ca channel opening, and MPT pore closing promote an increase in cardiac tolerance to I/R [123,142,143].…”

Dynamic Changes in Ion Channels during Myocardial Infarction and Therapeutic Challenges

“…Maintaining mitochondrial volume homeostasis is essential for preserving vesicle integrity during membrane transport with high variations in ions and water, which is crucial for ATP generation [ 140 ]. Additionally, it helps in preventing the occurrence of ventricular arrhythmias and improving survival rates during cardiac I/R [ 141 ].…”