Functional protection against cardiac diseases depends on ATP‐sensitive potassium channels

Abstract ATP‐sensitive potassium channels (KATP) channels are widely distributed in various tissues, including pancreatic beta cells, muscle tissue and brain tissue. KATP channels play an important role in cardioprotection in physiological/pathological situations. KATP channels are inhibited by an increase in the intracellular ATP concentration and are stimulated by an increase in the intracellular MgADP concentration. Activation of KATP channels decreases ischaemia/reperfusion injury, protects cardiomyocytes from heart failure, and reduces the occurrence of arrhythmias. KATP channels are involved in various signalling pathways, and their participation in protective processes is regulated by endogenous signalling molecules, such as nitric oxide and hydrogen sulphide. KATP channels may act as a new drug target to fight against cardiovascular disease in the development of related drugs in the future. This review highlights the potential mechanisms correlated with the protective role of KATP channels and their therapeutic value in cardiovascular diseases.


| INTRODUCTION
Arrhythmia is a leading cause of mortality and morbidity in cardiovascular diseases. Several ion channels in cardiomyocytes shape action potentials, trigger electrophysiological activities, and excitation-contraction coupling (ECC), and finally, induce cardiac contraction and blood pumping within the circulatory system. Abnormal ion channels may affect cardiac function.
The ATP-sensitive potassium (K ATP ) channel was first identified by Noma in cardiomyocytes treated with hypoxia using the patch clamp technique in 1983. 1 K ATP channels are characterized by channel inhibition because of an increase in the intracellular ATP concentration and stimulation because of an increase in the intracellular MgADP concentration. [2][3][4] Cumulative evidence has indicated that K ATP channels, which are ATP-sensitive potassium channels, are widely distributed in various tissues, including pancreatic beta cells, muscle tissue, and brain tissue, and play an important role in cardioprotection in physiological and/or pathological states. Particularly, under pathophysiological conditions, K ATP channels play a critical protective role by regulating cardiac repolarization. Activation of K ATP channels decreases ischaemia/ reperfusion injury, protects cardiomyocytes during heart failure, and reduces the occurrence of arrhythmias.
K ATP channels couple the cellular metabolic state to the membrane potential. K ATP channels play a critical role in various cellular functions, including hormone secretion and regulation of muscle excitability. K ATP channels are also the target of endogenous vasoactive substances, such as nitric oxide (NO), reactive oxygen species (ROS), and hydrogen sulphide (H 2 S). 5,6 The protective mechanisms of K ATP channels involve various signalling pathways. K ATP channels may act as a new drug target to fight against cardiovascular disease in the development of drugs in the future. This review highlights a potential mechanism correlated with the protective role of K ATP channels and their therapeutic value in cardiovascular diseases.

| PROPERTIES OF K A T P CHANNELS
Many K + channels are regulated by voltage and/or Ca 2+ and are named Kv or KCa channels respectively. 7-9 A group of K + channels that is not regulated in this manner is the inward rectifier K + channel (Kir channels). K ATP channels are composed of four Kir channel subunits, Kir6.x (Kir6.1 and Kir6.2 are encoded by KCNJ8 and KCNJ11, respectively), and four sulphonylurea receptors, SUR (SUR1 and SUR2, with two splice variants: SUR2A and SUR2B, which are encoded by ABCC8 and ABCC9, respectively), whose subunit composition exhibits tissue specificity 10,11 (see Table 1). SUR has three domains that include TMD0, TMD1, and TMD2 helices. TMD1-TMD2 and the C-terminus contain nucleotide-binding domains (NBD1 and NBD2) 12,13 (see Figure 1). The Kir subunit contains two transmembrane regions, a pore-forming loop and cytosolic NH 2 and COOH termini, whereas the Kv (voltage-gated K + ) channel subunit possesses six transmembrane regions, which include an ion conduction pore and voltage-sensor domains 14 (see Figure 2).  Table 2). The Kir6.2 subunit has more intrinsic sensitivity to cellular metabolic disorders than the Kir6.1 subunit. 16 In addition, the composition of the mitochondrial K ATP (mitoK ATP ) channels is still unclear, although some literature suggests that Kir6.1 may be a functionally important part of mitoK ATP channels in native heart cells. 17

| CARDIAC DISEASES
The opening and closing of K ATP channels are regulated by various signalling molecules, including membrane phosphoinositides, the intracellular ATP concentration, and MgADP. 18 Small signalling molecules, such as NO, H 2 S, and ROS, also play critical roles in protecting the cardiovascular system by regulating K ATP channels. 5,6 H 2 S is endogenously generated from cysteine metabolism. Zhao et al 6 reported that H 2 S directly increased K ATP channel currents and hyperpolarized membrane and relaxed rat aortic tissues in vitro in a K ATP channel-dependent manner. These results demonstrated that H 2 S is an important endogenous vasoactive factor and a gaseous opener of K ATP channels in vascular smooth muscle cells, but their mechanisms of action remain unclear. Zhang et al 5 found that NO, a gaseous messenger known to be cytoprotective, increased the activity of K ATP channels. These changes were reversed in the presence of inhibitors that were selective for PKG, ERK, calmodulin, or genetic ablation of CaMKIIδ, the predominant cardiac CaMKII isoform. These experimental results indicate that NO modulates K ATP channels via a novel PKG-ERK-calmodulin-CaMKIIδ signalling pathway. 5

| Cardiomyopathy
The opening of K ATP channels protects cardiac muscle cells against hyperglycaemia-induced damage and inflammation by inhibiting the ROS-activated TLR4-necroptosis pathway, which may be an important underlying mechanism of ROS in diabetic cardiomyopathy.
These results indicated the cardio-protective effects again injury induced by ROS in a KATP channels-dependent manner. 19 Some binding sites in K ATP channels combine with signalling molecules to regulate the activity of K ATP channels. Burton et al 20 found that cardiac K ATP channels were regulated by heme, and the cytoplasmic heme-binding CXXHX16H motif on the SUR subunit of the channel was shown to include Cys628 and His648, which are important for heme binding. These results supported the hypothesis that there are mechanisms of heme-dependent regulation across other ion channels.
Activation of α 1 -adrenoceptors by pretreatment with phenylephrine can up-regulate SUR2B/Kir6.2 to participate in cardio-protection in H9C2 cells. 21 This study showed that the up-regulation of SUR2B/Kir6.2 might have a different physiological consequence from the up-regulation of SUR2A/Kir6.2. This is the first explanation for the possible physiological role of SUR2B in a cardiac phenotype.
Syntaxin-1A interacts with SUR2A to inhibit K ATP channels, and PIP 2 is known to bind the Kir6.2 subunit to open K ATP channels. By contrast, it is interesting that PIP2 affects K ATP channels by dynamically modulating Syn-1A mobility from Syn-1A clusters, resulting in the availability of Syn-1A to inhibit K ATP channels on the plasma membrane. This differential effect is related to the concentration of PIP 2.

22
Evidence demonstrates that stretch-induced K ATP channel activity is controlled by MgATPase activity. These results may explain how K ATP channel activity might respond rapidly to changes in the cardiac workload in a healthy heart and in a pathological state. 23

| Cardiac arrhythmias
Cardiac K ATP channels have emerged as crucial controllers of heart failure and ischaemia-related cardiac arrhythmias and have been suggested to be responsible for cardioprotection by decreasing repolarization dispersion and promoting action potential shortening. [25][26][27] In cardiomyocytes, the ability of the mitochondrial network, which restores energy production and limits necrotic and apoptotic cell death, is a key determinant of survival after ischaemia-reperfusion (IR). Mitochondrial function is a major factor in arrhythmogenesis during IR. Mitochondrial uncoupling can alter cellular electrical excitability and increase the propensity for reentry through opening of sarcolemmal K ATP channels. Mitochondrial inner membrane potential (ΔΨm) is an essential component in the process of energy storage. ΔΨm instability or oscillation induced by ROS led to cardiac arrhythmia. This mechanism is necessary to increase the dispersion of refractoriness, slow the conduction velocity, and create a regional excitation block. 28 Recent data have shown that mutations of K ATP channels in myocardial cells can directly result in arrhythmias. The E23K variant of KCNJ11, identified in patients with type 2 diabetes, 29 results in the frequent opening of K ATP channels, which is associated with a greater left ventricular size with hypertension. 30 These mutations, in turn, increases the occurrence of ventricular arrhythmias (VA) in dilated cardiomyopathy patients. Moreover, a KCNJ8 mutation was also found to be associated with atrial fibrillation (AF), and K ATP channel currents were found to be decreased during chronic human AF. 31 Feng et al 32

| Mutations in human disease
Patients with Cantu syndrome, which is caused by gain-of-function (GOF) mutations in genes encoding Kir6.1 and SUR2, have enlarged hearts with an increased ejection fraction and increased contractility.
Mice with cardiac-specific Kir6.1 GOF subunit expression show left ventricular dilation and increased basal L-type Ca 2+ currents, which results in phosphorylation of the pore-forming α 1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928 relative to that in WT mice treated with isoproterenol. 34 This result suggests that increasing protein kinase activity may act as a potential connection between increased K ATP current and cardioprotection.

| DRUG THERAPY AND PERSPECTIVE
K ATP channels, a major drug target for the treatment of T2DM, are crucial in the regulation of heart injury and vascular smooth muscle tone. K ATP channels are also important since the therapeutic agents that target K ATP channels can also treat cardiovascular diseases. New effects correlated with K ATP channels have recently been identified that were previously undetected. For example, the volatile anaesthetic isoflurane preserves the normalization of human K ATP channel activity in human arteries exposed to oxidative stress caused by high glucose. 35 Isoquercitrin induces vasodilation in resistance arteries, an effect that is mediated by the opening of K ATP channels and endothelial NO production. 36 Treatment with one type of fatty acid, EPA, in the early phase of myocardial infarction significantly reduces cardiac mRNA and protein expression of Kir6.2 and increases the SUR2B subunit. These findings indicate that EPA may suppress acute phase fatal VA and may have an inhibitory effect on ischaemia-induced ventricular fibrillation in vivo, which may be mediated by an enhancement of ischaemiainduced monophasic action potential shortening. 37 Epoxyeicosatrienoic acids, metabolites of arachidonic acid, are involved in the activation of PI3Kα and opening of K ATP channels, which prevent Ca 2+ overload and maintain mitochondrial function. 38 Isosteviol sodium may increase the activation rate of sarcK ATP channels induced by pinacidil and potentiate the diazoxide-elicited oxidation of flavoproteins in mitochondria. 39 The new antihypertensive drug iptakalim activates K ATP channels in the endothelial cells of resistance blood vessels, a mechanism that is dependent on ATP hydrolysis and specific ATP ligands. The functions of endothelial K ATP channels in resistance blood vessels can be changed by the exposure to the high shear stress caused by hypertension. 40 Sulfonylurea induces the release of insulin by inhibiting the K ATP channels that are present in pancreatic beta cells. Under high glucose conditions, glucose promotes the synthesis of intracellular ATP, which blocks K ATP channels and prevents K + efflux, leading to membrane depolarization and the opening of Ca 2+ channels, allowing an influx of calcium and release of insulin. 41,42 Although efforts to reduce cardiovascular mortality in patients with diabetes mellitus should focus on improving glycaemic control, there is controversy as to whether the use of sulfonylurea increases the susceptibility of the myocardium to ischaemic insult, in light of the functional mechanisms of sulfonylurea drugs, which act through inhibition of the K ATP channels present in both pancreatic beta cells and cardiomyocytes. [25][26][27]43,44 Cardiac K ATP channels inhibited by sulfonylurea drugs may be harmful to the ischaemic myocardium because of a disturbed K ATP channel dependent response in the ischaemic precondition response. 26 Further research is needed to develop a "selective" drug that targets pancreatic KATP channels without affecting cardiac channels.
It is clear that K ATP channels play a significant role in the protection against cardiovascular diseases. In the literature, there is a considerable volume of information available regarding the mechanism of the protective role of K ATP channels under different pathophysiological conditions, such as I/R injury, heart failure, cardiac arrhythmias, and atherosclerosis. However, studies characterizing K ATP channels in targeted therapy of patients as well as the research and development of efficacious therapies are sparse, and further studies should investigate the potential mechanisms of K ATP channels in cardiovascular diseases.

CONFLI CT OF INTEREST
The authors declare that they have no conflict of interest.