Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat

Abstract

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

miR-125a, miR-139 and miR-324 contribute to Urocortin protection against myocardial ischemia-reperfusion injury

“…Moreover, miR-324-3p overexpression downregulated NFAT5 and CASQ1 genes, whose role in cardioprotection are unknown. Although, NFAT5 expression was increased during protection against hypertonicity during I/R in rat kidney 53 ; whereas, CASQ1 is a calcium-regulating protein involved in cardiac myocyte contraction, whose alteration was associated with Ca 2+ overload during I/R 54 .…”

“…Male Wistar rats weighing 250 ± 50 grams were anesthetized with a mixture of O 2 /sevoflurane 2%, then with anesthesia (50 mg/kg ketamine plus 8 mg/kg xylazine i.p) as described previously 54 . A small animal ventilator was used (Harvard Apparatus, Model 683, Massachusetts, NC) with a tidal volume (Vt) of 1.60–2 ml and 75–80 ventilations per minute.…”

Electrocardiography in Rats: a Comparison to Human

“…This is because rats' hearts do not express the human Ether-à-go-go-Related Gene (hERG), whereas drugs cardiotoxicity is strongly associated with blocking of hERG-related potassium channels (De Bruin et al 2005). However, the rats' hearts express a variant of Ether-à-go-go-Related Gene (rat ERG, also known as Kcnh2) (Matus et al 2015), which may play a role in drug induced cardiotoxicity, but further research is needed to support this notion.…”

Contractile and electrical activities of dexchlorpheniramine on rat hearts

“…This is because rats' hearts do not express the hERG. However, the rats' hearts express a variant of Ether-a-gogo-Related Gene (rat ERG, also known as Kcnh2), 26 which may play a role in drug induced cardiotoxicity, but further research is needed to support this notion.…”