As an independent factor associated with high mortality, acute myocardial infarction is an irreversible process characterized by glycogen depletion, margination of nuclear chromatin, mitochondrial swelling and sarcolemmal breaks. Myocardial infarct size and the duration of ischemia are the main determinants of the prognosis (Heusch, 2020). Rapidly restoring blood flow is the key to successful salvage of ischemic myocardium; however, reperfusion not only salvages ischemic myocardium from infarction but also induces an increased risk of additional complications and further cardiomyocyte death, a process called myocardial ischemia reperfusion injury (MIRI) (Griffiths et al., 2021). In myocardial ischemia, the mitochondrial matrix is damaged and extensively broken, and it dissolves the mitochondrial crest, ruptures and vacuolates the mitochondrial membrane, significantly decreases glycogen granules, increases intracellular Ca²⁺, diminishes ATP production, and induces myocardial cell apoptosis (Paggio et al., 2019; Basalay et al., 2020; Wang et al., 2020; Bai et al., 2021; Wang et al., 2021). A novel autologous mitochondrial transplantation therapy, in which respiration-competent mitochondria are isolated from autologous nonischemic tissue and transplanted into ischemic myocardium, improves the contractile function and tissue viability of the injured myocardium, proving that mitochondrial injury is the main pathogenesis of MIRI (Shin et al., 2019).

mitoK_ATP channels are involved in a series of physiological and pathophysiological changes to mitigate cardiomyocyte injury and apoptosis. mitoK_ATP channels have been described as being located in the inner mitochondrial membrane and they have protective properties for ischemic myocardium; moreover, their existence has been the subject of heated debate (Bezerra Palácio et al., 2021). Recently, the molecular composition of mitoK_ATP was shown by Paggio et al., and they are comprised of pore-forming (MITOK, encoded by the CCDC51 gene (NCBI ID 79714)) and regulatory (MITOSUR, tissue expression correlates with ABCB8) subunits (Paggio et al., 2019) (Figure 2). The opening of mitoK_ATP channels promotes mitochondrial K⁺ inward flow into the deeply negative polarized matrix (mitochondrial membrane potential (Ψ _m)), decreases the transmembrane potential discrepancy, depolarizes the Ψ _m, reduces Ca²⁺ inward flow dynamics, inhibits Ca²⁺ inward flow, and prevents mitochondrial calcium overload, leading to mitochondrial relaxation, enhanced fatty acid oxidation, oxidative phosphorylation, respiratory function, and ATP production, thus improving myocardial cell survival (Sakamoto and Kurokawa, 2019; Jiang et al., 2021).

During the process of MIRI, the activation of mitochondrial K_ATP channels depolarizes the mitochondrial membrane, reduces the driving force of mitochondrial calcium uptake, and prevents Ca²⁺ accumulation in the mitochondrial matrix, thus preventing the formation of the mitochondrial permeability transition pore (MPTP) (Testai et al., 2021). Currently, the main components of MPTP are as follows: adenine nucleotide translocator (ANT) and mitochondrial phosphate carrier (PiC) on the inner mitochondrial membrane (IMM), mammalian F1Fo(F)-ATP synthase (the Fo subunit consists of a, e, f, g and A6 L; the F1 subunit α, β, and the ε and γ subunits needed for ATP synthase dimer formation, the peripheral stem consists of b, d, and the F6 subunit and oligomycin sensitivity conferring protein (OSCP)) (Kent et al., 2021) (Figure 2). MPTP is the point at which reactive oxygen species (ROS), Ca²⁺, cytochrome C (Cyt C), and other small molecule modulators escape from the mitochondrial matrix, and its opening leads to the loss of oxidative phosphorylation capacity as well as the release of pro-death mitochondrial proteins (mitochondrial swelling and membrane rupture), increased Bax expression and decreased Bcl₂ expression, ultimately activating the apoptotic cascade in the mitochondria in ischemia–reperfusion heart tissues (Jiang et al., 2021; Kent et al., 2021; Pereira and Kowaltowski, 2021). Mitochondrial ROS spreading from the electron transport chain damages the mitochondrial DNA, which can cause mitochondrial dysfunction and affect nuclear gene expression, ion handling, and mitochondrial metabolism, finally causing the activation of an inflammatory response, apoptotic signaling, and endoplasmic reticulum stress in the cardiovascular system (Bou-Teen et al., 2021). Indeed, MIRI triggers a cascade involving increased NO production (NO function; anti-inflammatory and antioxidant effects) and leads to the superfluous formation of peroxynitrite (ONOO⁻) with increased production of ROS, which mediates the pernicious impact of NO (Liu et al., 2021a). The activation of mitoK_ATP during ischemia plays a role in the cardioprotective function by inhibiting the overproduction of ROS and stimulating the NO effects on anti-inflammatory and antioxidant activities in the ischemic myocardium (Liu et al., 2021a; Rameshrad et al., 2021). Ischemic postconditioning activates protein kinase C and reperfusion injury salvage kinase pathways through modulating the intracellular concentrations of adenosine and NO, ultimately acting on the mitoK_ATP pathway to protect the myocardium (Li et al., 2020a).

mitoK_ATP channels also affect other cardiac components. Within rat cardiac fibroblasts (CFs), mitoK_ATP channels prevent the transdifferentiation of CFs to myofibroblasts (MFs) to reduce MF maturation and antagonize cardiac pathological remodeling following simulated ischemia-reperfusion injury (Stewart and Turner, 2021). ROMK (a kidney mRNA detectable in the thick ascending limb and the distal nephron) participates in K⁺ reabsorption and secretion. An experiment performed by Irina B. Krylova et al. implicated ROMK in Ca²⁺-induced MPTP opening but did not play a role in mitoK_ATP activity in the mouse heart (Papanicolaou et al., 2020). Electrophysiological analysis revealed that 10 μM testosterone increased the open probability of mitoK_ATP channels, which offered cytoprotection against MIRI (Sakamoto and Kurokawa, 2019).

The recently discovered signal-regulated pathways involved in mitoK_ATP channels are as follows. Penehyclidine hydrochloride (PHC) preconditioning plays a cardioprotective role by regulating the mitochondrial K_ATP channel and Akt/GSK-3β and Akt/mTOR signaling pathways (Zi et al., 2020). Uridine attenuates myocardial injury and oxidative stress in MIRI, which may be mediated by activation of the mitoK_ATP channel, achieved by reducing excessive ROS production and preventing the appearance of calcium overload (Krylova et al., 2021). GST (genistein, a phytoestrogen) provides a cardioprotective function that depends on protein kinase C and activates mitoK_ATP channels via a typical pathway, such as PI3K/Akt and NO synthases (Colareda et al., 2020).

Early evidence indicated that sarcolemma ATP-sensitive potassium (sarcK_ATP) channels play a crucial role in ischemic preconditioning and myocardial resistance to ischemia, which close during general conditions and open in response to increased [ADP]/[ATP], linking membrane excitability to the balance of ATP production and shortening action potential (AP) duration (APD) via the efflux of K⁺ (Garrott et al., 2017; Sudhir et al., 2020). SarcK_ATP channels improve adaptation to physical stress and profoundly alter membrane excitability and other membrane potential-related functions, such as Ca²⁺ overload, thus helping to maintain cellular homeostasis during cardiac challenge (i.v. adenosine) (Zhang et al., 2016). The partial opening of sarcK_ATP channels plays a crucial role in the regional depolarization of Ψm, which can transform cellular electrical excitability and increase the propensity for reentry arrhythmogenesis (Solhjoo and O'Rourke, 2015). An unstable or oscillating Ψm can expose cardiomyocytes to ROS or result in glutathione depletion, activate sarcK_ATP channels and abate the cellular ATP/ADP ratio, which has been deemed to be a dominant factor in arrhythmogenesis during MIRI (Solhjoo and O'Rourke, 2015).

Increased activation of the sarcK_ATP channel (a role in cardioprotection) does not participate in the protection provided by ordinary cardioprotective stimulation_. sarcK_ATP opening actually occurs later during metabolic inhibition (after cardioprotection), cardioprotective stimuli prolong normal mitochondrial function during ischemia, and the delay in the opening of sarcK_ATP channels is a consequence of the continuation of ATP production, so sarcK_ATP channel opening is the last defense of cardiomyocytes to preserve ATP and limit the Ca²⁺ overload during ischemia (Brennan et al., 2015). The density of sarcK_ATP channels under physiological conditions plays a significant role in cardioprotection; however, certain pathophysiologic circumstances give rise to a declining density of sarcK_ATP channels, including hyperinsulinemia and cardiac ischemia (Yang et al., 2018). The lower basal expression level of sarcK_ATP channels in hESCs (human embryonic stem cells)-VCMs (ventricular cardiomyocytes) (∼1/8 of adults) means they were partially activated and sufficient to cause APD shortening and accelerate AP firing; when fully activated, sarcK_ATP channels silenced automaticity without compromising intrinsic cellular excitability (Keung et al., 2016).

Studies on the cardiac sarcK_ATP channel regulatory subunit SUR2A/SUR2B are ongoing. The activation of ß ₁-adrenoceptors upregulates SUR2B/Kir6.2, in which SUR2B physically associates with Kir6.2 to act as a regulatory subunit in sarcK_ATP channels to offer cardioprotection (Jovanovic et al., 2016). With an increasing number of sarcK_ATP channels, increased expression of SUR2A regulates cardiac physiology and improves the adaptation to physical stress by shortening the action potential and improving cardiac Ca²⁺ homeostasis (Zhang et al., 2016).

The recently discovered signal-regulated pathways and regulatory proteins involved in sarcK_ATP channels are as follows. Eps15 homology domain-containing protein (EHD)-2 affects the sarcK_ATP channel by stabilizing sarcK_ATP channel-containing caveolar structures to increase its surface density, which results in a reduced rate of endocytosis. Pathophysiologically, EHD-2 mutant-activated cardiomyocytes may be cardioprotective against ischemic damage (Yang et al., 2018). In rat cardiomyocytes, the sarcK_ATP channel exerts a cardioprotective effect against lipopolysaccharide (LPS)-induced apoptosis and it is mediated by mitochondrial Ca²⁺ (Zhang et al., 2016). The cardioprotective effect of BNP is related to sarcK_ATP channel opening. Additionally, the cardioprotective effects of ANP and cANP4-23 are mediated via sarcK_ATP channel opening (Krylatov et al., 2021). ANP (atrial natriuretic peptide) positively regulates the function of the sarcK_ATP channel in adult rabbit ventricular cardiomyocytes by activating NPR-A (natriuretic peptide receptor type A), an effect mediated by intracellular signaling mechanisms that cover PKG (cGMP-dependent protein kinase), ROS, ERK (extracellular signal-regulated protein kinase)1/2, CaMK II (calcium/calmodulin-dependent protein kinase II), and RyR (ryanodine receptor)-2; meanwhile, RyR2 (activation) is feasibly situated downstream of ROS/H₂O₂, which process enhances the opening frequency whereas it labilizes the long closures of the channel, thereby heightening channel activity (Zhang and Lin, 2020).

Endothelium-expressed Kir6.1 is located on human chromosome 12p, and via elevated endothelin-1 release it controls vascular tone. Smooth muscle Kir6.1 gain-of-function mutation causes overt hypertension and hypotension; notably, autosomal dominant hypertension is related to chromosome 12p recombination, and postural hypotension is related to chromosome 12 (Li et al., 2013) (Table 2). In gain-of-function mutation Kir6.1 [GD-QR] (point mutations in two C-terminal residues of Kir6.1; Gly343Asp and Gln53Arg), lymphatic smooth muscle and vascular dysfunction are present, and lymphatic smooth muscle-specific expression subunit mutations result in profound lymphatic contractile dysfunction and lymphatic smooth muscle hyperpolarization rather than lymphatic endothelial cells (Davis et al., 2020). In a CS animal model, the Kir6.1^wt/VM mutation directly and/or indirectly affects the skeletal muscle through vascular dysfunction, resulting in reduced limb strength, skeletal muscle atrophy, autophagy, and myofiber connective tissue replacement (Scala et al., 2020). The S422 L mutation, a missense mutation in the KCNJ8 gene, leads to a gain-of-function Kir6.1 channel, which leads to shortened repolarization in ventricular tissue; nevertheless, it could shorten repolarization in the atrium to increase atrial fibrillation susceptibility (Delaney et al., 2012).

Approximately 38.5% of mutations in the KCNJ11 gene, which encodes Kir 6.2 and consists of a single exon containing 390 amino acids, have been identified, which is associated with clinical diseases including but not limited to neonatal diabetes mellitus, maturity-onset diabetes of the young, type 2 diabetes mellitus, and even persistent hyperinsulinemic hypoglycemia of infancy (He et al., 2021). Patients with the E227K mutation in the KCNJ11 gene typically manifest with transient neonatal diabetes, which remits spontaneously, usually within 4–60 weeks of onset; however, more than half of these patients relapse into permanent diabetes in adolescence or early adulthood (Devaraja et al., 2020). rs5215 G/G (nucleotide change; G-A, amino acid change; Val337Ile) of the KCNJ11 gene, located at 11p15.1 and encoding the Kir6.2 subunit, causes valine-isoleucine substitution in exon 1,009 (ATC-GTC), and it is associated with a gain of function of the K_ATP channel, leading to vasodilation augmentation and shear stress reduction, which protects humans from lower coronary microvascular dysfunction, reducing the risk of ischemic heart disease in women (Severino et al., 2020). In a hypertension mouse model, the Kir6.2 mutation led to heart failure and death, involving knockout mutation-induced myocardial incommensurate remodeling (Liu et al., 2021b). In neurons, Kir6.2 has critical roles in glucose sensing and neuronal excitability in response to metabolic demands, and the KCNJ11 p. V59 M mutation was strongly associated with intellectual disability (Moriguchi et al., 2018; Svalastoga et al., 2020).

SUR1 is mainly expressed in the pancreas, and its mutations may lead to neonatal diabetes by disrupting inhibitory binding/gating or enhancing nucleotide stimulation. Some SUR1 mutant models in mice did not recapitulate the human phenotype (Sachse et al., 2020; Usher et al., 2020). SUR1-mutant (a homozygous c.560T > A (V187D) mutation in exon four of the ABCC8 gene encoding the SUR1 protein) stem cell-derived islet-like clusters (SC islets) leads to increased beta-cell proliferation and mass, higher insulin secretion in hypoglycemia and makes K_ATP channels-acting pharmaceuticals ineffective (Lithovius et al., 2021). The homozygous p. H1401Tfs ABCC8 mutation could cause significant clinical heterogeneity congenital hyperinsulinemia, ranging from a late-onset and diazoxide-responsive mild form to an extremely early-onset severe form requiring multimodality treatment with a full-course assessment of neurodevelopment and glycometabolism (Takasawa et al., 2021). Some SUR1 mutations resulted in increased channel activity in MgATP/MgADP and drastically reduced K_ATP channel surface expression, which suggests that the overactive defects due to altered nucleotide sensitivities outweigh their biogenesis and surface expression defects and lead to an overall gain-of-channel-function effect and the neonatal diabetes mellitus disease phenotype (Balamurugan et al., 2019).

Due to the strong difficulties and inferior feasibility of single subunit mutation research, we mainly noted several common cases herein. In individuals with idiopathic dilated cardiomyopathy, two heterozygous mutations in exon 38 of ABCC9 encode at the C-terminal domain of SUR2A, Fs1524 (a frameshift at Leu1524, which introduces four anomalous terminal residues followed by a premature stop codon) and A1513T (a missense mutation (4537G→A) causing the amino acid substitution), substantially diminishing the maximal rate of the NBD2 ATPase reaction without altering the Michaelis-Menten constant of catalysis, resulting in abnormal hydrolytic dynamics of the regulatory channel subunits, disrupting catalysis-dependent gating and impairing metabolic decoding, resulting in severely dilated hearts with impaired systolic function and arrhythmia (Bienengraeber et al., 2004).

The SUR2B mutation R659C located in the secondary structure region in the L1 linker (it has the greatest α-helical propensity) most stably interacts with NBD1, which could cause heart disease and even lead to early repolarization syndrome, a life-threatening condition (Sooklal et al., 2018). During colonic inflammation, two specific mutations within SUR2B (C24S and C1455S) prevent the detrimental effects of sulfhydration and NaHS-induced tyrosine nitration from reducing the pore-forming subunit (Kir6.1) (Kang et al., 2015).

Cantú syndrome (CS) is an ultrarare autosomal dominant inherited disorder caused by dominant gain-of-function mutations in both the SUR2A and Kir6.1 subunits of the K_ATP channel, which is also characterized by multiple cardiovascular abnormalities, including edema, pericardial effusion, pulmonary hypertension, dilated and tortuous blood vessels with decreased systemic vascular resistance, cerebrovascular defects, patent ductus arteriosus, and marked cardiac hypertrophy (Chen et al., 2019; Chihara et al., 2020; McClenaghan et al., 2020; Zhang et al., 2021a) (Table 3). CHI is a rare genetically heterogeneous disorder caused by inactivating mutations in the SUR1 and Kir6.2 subunits of the K_ATP channel and it is characterized by persistent hypoglycemia in infants and children, which may increase the risk of permanent brain damage (Boodhansingh et al., 2019; Rosenfeld et al., 2019; Männistö et al., 2020; Rosenfeld et al., 2021). NDM is characterized by the development of hyperglycemia within the first 6 months of life, beta-cell destruction, pancreatic hypoplasia or aplasia, impaired beta-cell function or severe insulin resistance resulting from impaired insulin secretion caused by gain-of-function mutations in KCNJ11 and/or ABCC8 subunits of the K_ATP channel, which can be divided into two transient diabetes mellitus (TNDM) and perma-nent diabetes mellitus (PNDM) clinical subtypes, depending on the length of the disease course (Cao et al., 2020; Dahl and Kumar, 2020; Pipatpolkai et al., 2020; Horita et al., 2021). DEND syndrome is a severe pathological condition of neonatal diabetes with developmental delay, muscle weakness, and epilepsy caused by gain-of-function mutations in Kir 6.2 and SUR1 (Dahl and Kumar, 2020; Pipatpolkai et al., 2020; Gopi et al., 2021). AIMS is characterized by delayed psychomotor development with intellectual disability, anxiety, muscle weakness and fatigability and some shared dysmorphic features caused by loss-of-function mutations in ABCC9 (SUR2A and/or SUR2B) (Smeland et al., 2019).

Hydrogen sulfide (H₂S), as a gaseous signaling molecule, has a wide range of biological functions, including vasodilatation, anti-endoplasmic reticulum stress, anti-apoptotic and anti-inflammatory functions, and it contributes to ameliorating ventricular structural remodeling and cardiac function (Li et al., 2021). In cardiac tissue, the most important enzyme for the synthesis of H₂S is cystathionine γ-lyase (CSE), which has reduced activity in atherosclerotic patients connected with angina and atrial fibrillation (Bibli et al., 2021) (Figure 3). H₂S has many significant bioactivities, including cytoprotective, antioxidant, anti-inflammatory, anti-apoptotic, and smooth muscle relaxing effects, in part because it acts as a K_ATP channel opener (Fouad et al., 2020). H₂S partially inhibits phosphodiesterase-5 through the activation of K_ATP channels and increases intracellular cGMP to evoke direct vasorelaxing responses (Citi et al., 2020). H₂S activates the K_ATP channel and inhibits insulin secretion in INS-1E cells (a pancreatic ß-cell line), but the function of hyperpolarizing the plasma membrane and closing voltage-gated Ca²⁺ channels is not mediated by the K_ATP channel (Lu et al., 2019; Shoji et al., 2019). H₂S modulates K_ATP channel activity, promotes protective effects against pulmonary hypertension and increases uterine blood flow by antagonizing vasoconstriction (Guerra and Hurt, 2019; Roubenne et al., 2021). H₂S protects the embryonic heart from I/R injury by opening the K_ATP channel rather than increasing coronary artery flow, demonstrating that H₂S treatment of the embryonic heart is independent of the mother and the underdeveloped placenta (Hess et al., 2020). NaHS, a rapid-releasing H₂S donor, stimulates ANP secretion via the K_ATP channel under hypoxic conditions, resulting in decreased blood pressure, ECF volume and antiproliferation of vascular smooth muscle cells in the cardiovascular system (Yu et al., 2019). Briefly, the interaction between H₂S and K_ATP plays an irreplaceable role in cardiovascular disease.

The NO-cyclic guanosine monophosphate (cGMP) signaling pathway is a potential therapeutic target for heart failure, and a reduction in NO bioavailability may result in the decreased production of cGMP, which could lead to decreased protection against myocardial injury, vascular and ventricular sclerosis, fibrosis, hypertrophy, and cardiorenal syndrome (Udelson et al., 2020). K_ATP channels can activate the L-arginine/NO/cGMP cascade pathway to induce membrane hyperpolarization, which results in shortening the action potential and restricting Ca²⁺ entry through Ca²⁺ channels, thus contributing to cardioprotection and vasodilatation (Wang et al., 2019a; Iguchi et al., 2019). Reductions in the arterial blood pressure effect of white mulberry fruit polysaccharides, the vascular relaxation effect of tetrahydropalmatine on rat aortae, and the vasodilatory effect of formaldehyde, either partially or completely, are all mediated by the NO/cGMP/K_ATP pathway (Wang et al., 2019a; Zhou et al., 2019a; Zhao et al., 2019). Lipofundin MCT/LCT is involved in attenuating K_ATP channel-induced vasodilation by inhibiting basally released endothelial NO and/or cGMP (Lee et al., 2020). The antinociceptive effects of methanol extracts of B. spectabilis, cardamonin and Lonchocarpus araripensis lectin ether are partially or completely mediated by the NO/cGMP/K_ATP pathways (Assreuy et al., 2020; Ferdous et al., 2020; Pui Ping et al., 2020). The K_ATP channel, a gastroprotective factor, is involved in the gastroprotective effects of N-acylarylhydrazone derivatives on ethanol-induced gastric lesions in mice via the NO/cGMP pathway (da Silva Monteiro et al., 2019). Therefore, the NO/cGMP/K_ATP pathway is involved in a variety of organoprotective and vasodilative pharmacological processes.

The heart operates exclusively under aerobic metabolism and three factors, heart rate, contractility, and ventricular wall tension, require myocardial mitochondria for maintaining sufficient O₂ to sustain oxidative phosphorylation. Hypoxia causes the opening of the K_ATP channel due to a decline in the ATP:ADP ratio, which couples cellular metabolism to excitability to prevent action potential generation and cell contraction, ultimately leading to coronary artery smooth muscle cell hyperpolarization and the closure of voltage-dependent Ca²⁺ channels and relaxation (Yang et al., 2020a). Vascular K_ATP channels supporting skeletal muscle convective and diffusive O₂ transport and oxidative phosphorylation sustain submaximal exercise tolerance; conversely, K_ATP channel inhibitors may exacerbate exercise intolerance in healthy rats (Colburn et al., 2020). Additionally, K_ATP channel activation modulates the anterior circulation and total cerebral perfusion, contributing to cerebral blood flow and oxygen delivery responses to hypoxia, maintaining a constant cerebral blood supply, avoiding disturbances in the precise regulation of cerebral perfusion and oxygen delivery, and preventing severe tissue damage and even death (Smith et al., 2020).

CORM-3, a water-soluble CO-releasing molecule that can mimic the HO-1/CO (heme oxygenase-1/carbon monoxide) pathway by liberating CO under appropriate conditions in biological systems, activates mitoK_ATP channels and elicits cardioprotection against hypoxia-reoxygenation injury by inhibiting a bicarbonate transporter (most likely Na⁺/HCO3⁻) during reoxygenation (Portal et al., 2019). CORM-2 increases the gastric mucosal CO content and blood carboxyhemoglobin concentration, resulting in gastroprotection, alleviation of gastric lesions, decreased gastric DNA oxidation and the inflammatory response at the systemic level, which is partly mediated by K_ATP channels (Li et al., 2019). Sulfur dioxide (SO₂), a major toxic gas and environmental pollutant, plays a vasodilatory role through K_ATP channel activation in the peripheral cardiovascular system at high concentrations (>500 μmol/L) (Magierowska et al., 2019). The search for signaling molecular regulatory pathways related to K_ATP channels is still in progress.

Highly specific HCN 2 (hyperpolarization-activated, cyclic-nucleotide gated channels 2) in ventricular myocytes, an integral part of ventricular electric remodeling, and the reduced expression of its mRNA, leads to the downregulation of the K_ATP channel current, which is one of the partial causes of arrhythmia in diabetic rats (Hadova et al., 2021; White et al., 2021). Exogenous cholesterol eliminated the increase in SUR2, suggesting that cholesterol may regulate K_ATP channel expression and explain why patients with hypercholesterolemia were also able to cope with ischemic events (Geiger et al., 2021). Low-density lipoprotein (LDL)5, the most negatively charged subfraction of circulating LDL, which has been considered a novel factor for predicting coronary vascular disease and stroke, prolongs the APD and increases the current density of K_ATP channels, and may induce arrhythmias (Ma et al., 2020). Under 5-Hz pacing conditions, the ATP-sensitive potassium current of ZFHX3 knockdown (zinc finger homeobox three gene) cells was increased compared with that under other conditions, confirming that ZFHX3 knockdown and tachypacing are related to increased stress (Lkhagva et al., 2021). Statins increased the ADP/ATP ratio and activated K_ATP channels to dedifferentiate myofibroblasts, while inhibition of K_ATP channels weakened the role of statin-induced myofibroblast dedifferentiation (Emelyanova et al., 2019). K_ATP channels participate in the cardiomyocyte-specific expression of photoinduced proton pump inhibitors, hyperpolarizing the intact heart to terminate ventricular arrhythmias (Funken et al., 2019). Resistin, secreted by PVAT (the fat reserve surrounding blood vessels consisting of fat cells, immune cells, fibroblasts, and endothelial cells), did not alter K_ATP channel-mediated relaxation in males, while K_ATP channel-mediated relaxation was significantly reduced in females (Small et al., 2019).