KCCs, NKCCs, and NCC: Potential targets for cardiovascular therapeutics? A comprehensive review of cell and region specific expression and function

Cardiovascular diseases, the leading life-threatening conditions, involve cardiac arrhythmia, coronary artery disease, myocardial infarction, heart failure, cardiomyopathy, and heart valve disease that are associated with the altered functioning of cation-chloride cotransporters. The decreased number of cation-chloride cotransporters leads to reduced reactivity to adrenergic stimulation. The KCC family is crucial for numerous physiological processes including cell proliferation and invasion, regulation of membrane trafficking, maintaining ionic and osmotic homeostasis, erythrocyte swelling, dendritic spine formation, maturation of postsynaptic GABAergic inhibition, and inhibitory/excitatory signaling in neural tracts. KCC2 maintains intracellular chlorine homeostasis and opposes β-adrenergic stimulation-induced Cl- influx to prevent arrhythmogenesis. KCC3-inactivated cardiac tissue shows increased vascular resistance, aortic distensibility, heart size and weight (i.e. hypertrophic cardiomyopathy). Due to KCC4's high affinity for K+, it plays a vital role in cardiac ischemia with increased extracellular K+. The NKCC and NCC families play a vital role in the regulation of saliva volume, establishing the potassium-rich endolymph in the cochlea, sodium uptake in astrocytes, inhibiting myogenic response in microcirculatory beds, regulation of smooth muscle tone in resistance vessels, and blood pressure. NKCC1 regulates chlorine homeostasis and knocking it out impairs cardiomyocyte depolarization and cardiac contractility as well as impairs depolarization and contractility of vascular smooth muscle rings in the aorta. The activation of NCC in vascular cells promotes the formation of the abdominal aortic aneurysm. This narrative review provides a deep insight into the structure and function of KCCs, NKCCs, and NCC in human physiology and cardiac pathobiology. Also, it provides cell-specific (21 cell types) and region-specific (6 regions) expression of KCC1, KCC2, KCC3, KCC4, NKCC1, NKCC2, and NCC in heart.