Insulin acts as an atypical KCNQ1/KCNE1‐current activator and reverses long QT in insulin‐resistant aged rats by accelerating the ventricular action potential repolarization through affecting the β₃‐adrenergic receptor signaling pathway

Abstract

Insufficient-heart function is associated with myocardial insulin resistance in the elderly, particularly associated with long-QT, in a dependency on dysfunctional KCNQ1/KCNE1-channels. So, we aimed to examine the contribution of alterations in KCNQ1/KCNE1-current (I Ks ) to the aging-related remodeling of the heart as well as the role of insulin treatment on I Ks in the aged rats. Prolonged late-phase action potential (AP) repolarization of ventricular cardiomyocytes from insulin-resistant 24-month-old rats was significantly reversed by in vitro treatment of insulin or PKG inhibitor (in vivo, as well) via recovery in depressed I Ks . Although the protein level of either KCNQ1 or KCNE1 in cardiomyocytes was not affected with aging, PKG level was significantly increased in those cells. The inhibited I Ks in β 3 -ARs-stimulated cells could be reversed with a PKG inhibitor, indicating the correlation between PKGactivation and β 3 -ARs activation. Furthermore, in vivo treatment of aged rats, characterized by β 3 -ARs activation, with either insulin or a PKG inhibitor for 2 weeks provided significant recoveries in I Ks , prolonged late phases of APs, prolonged QT-intervals, and low heart rates without no effect on insulin resistance. In vivo insulin treatment provided also significant recovery in increased PKG and decreased PIP2 level, without the insulin effect on the KCNQ1 level in β 3 -ARs overexpressed cells. The inhibition of I Ks in aged-rat cardiomyocytes seems to be associated with activated β 3 -ARs dependent remodeling in the interaction between KCNQ1 and KCNE1. Significant recoveries in ventricular-repolarization of insulin-treated aged cardiomyocytes via recovery in I Ks strongly emphasize two important issues: (1) I Ks can be a novel target in aging-associated remodeling in the heart and insulin may be a cardioprotective agent in the maintenance of normal heart function during the aging process. (2) This study is one of the first to demonstrate insulin's benefits on long-QT in insulin-resistant aged rats by accelerating the ventricular AP

Intracellular Redistribution of Left Ventricular Connexin 43 Contributes to the Remodeling of Electrical Properties of the Heart in Insulin-resistant Elderly Rats

“…In addition, the literature data have shown a correlation between reduced insulin sensitivity and heart dysfunction, at most, via an increase in the QT-interval (long-QT) not only in diabetic patients 28,29 but also in aged mammalians. 30,31 Therefore, we aimed to examine a possible correlation between aging and associated heart dysfunction, through contribution of long-QT, at least, via alterations in connexin statuses, including not only their protein expression levels but also their cellular localizations. So, here, we examined the contribution of changes in the expression levels of pCx43 and Cx43 as well as their cellular localization and distribution patterns in the left ventricular part of the heart from insulin-resistant elderly rats with an apparent long-QT in their surface ECGs (Aged-group; 24 months old).…”

STIM1-Orai1 interaction mediated calcium influx activation contributes to cardiac contractility of insulin-resistant rats

“…On the other hand, since heart weight/body weight measurement is not the gold standart in hyperthropy evaluation, we can still speculate that there might be compensatory heart hypertrophy in MetS animals in current study. Moreover, we demonstrated cardiac hypertrophy bu using echocardiography in MetS animals in our previous study [ 47 ]. Therefore, the higher blood pressure leves despite reduced contractile force can be related to compensatory hypertrophy in cardiomyocytes.…”

Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response

“…Thus, the cg01647172 is mapped to the 5' untranslated region of the gene Pleckstrin Homology Domain Containing A1 (PLEKHA1) and is found hypomethylated in OCD patients. Likewise, we observed that the hypomethylated CpG cg00382572 position is assigned to the KCNQ1 gene coding for the Kcnq1 potassium channel, which is located in the pancreas and has been also associated with diabetes [24][25][26][27][28][29] . Finally, the cg19069918 is located near the gene TRPM8, which has been long studied as a cancer biomarker, particularly in pancreatic cancer 30 .…”