title: Catecholaminergic-induced arrhythmias in failing cardiomyocytes associated with human HRCS96A variant overexpression.
abstract: The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers. In the present study, we assessed the molecular and cellular mechanisms underlying human arrhythmias by adenoviral expression of the human wild-type (HRC(WT)) or mutant HRC (HRC(S96A)) in adult rat ventricular cardiomyocytes. Total HRC protein was increased by ∼50% in both HRC(WT)- and HRC(S96A)-infected cells. The HRC(S96A) mutant exacerbated the inhibitory effects of HRC(WT) on the amplitude of Ca(2+) transients, prolongation of Ca(2+) decay time, and caffeine-induced sarcoplasmic reticulum Ca(2+) release. Consistent with these findings, HRC(S96A) reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRC(WT). Furthermore, the frequency of spontaneous Ca(2+) sparks, which was reduced by HRC(WT), was increased by mutant HRC(S96A) under resting conditions although there were no spontaneous Ca(2+) waves under stress conditions. However, expression of the HRC(S96A) genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca(2+) transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575, USA.
authors: Peidong
authors: P
authors: Han
authors: Wenfeng
authors: W
authors: Cai
authors: Yanru
authors: Y
authors: Wang
authors: Chi Keung
authors: CK
authors: Lam
authors: Demetrios A
authors: DA
authors: Arvanitis
authors: Vivek P
authors: VP
authors: Singh
authors: Shan
authors: S
authors: Chen
authors: Huiliang
authors: H
authors: Zhang
authors: Rongli
authors: R
authors: Zhang
authors: Heping
authors: H
authors: Cheng
authors: Evangelia G
authors: EG
authors: Kranias
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000235:genetics; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002395:Catecholamines; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004562:Electrocardiography; D015870:Gene Expression; D057809:HEK293 Cells; D006333:Heart Failure / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects*; D017354:Point Mutation / Q000235:genetics / Q000502:physiology; D011110:Polymorphism, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics
chemical_list: C506948:Atp2a2 protein, rat; D002135:Calcium-Binding Proteins; D002395:Catecholamines; D018076:DNA, Complementary; C500544:HRC protein, rat; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium