Affiliation:
1. From the Department of Medicine, Division of Cardiology (S.R.S., R.A., M.C., W.G.W., C.W.B.), Department of Pediatrics (J.M.B.), Department of Anatomy (J.M.S.), and the Department of Physiology (W.G.W., C.W.B.), The University of Maryland School of Medicine, Baltimore, Md, and Krannert Institute of Cardiology (B.A.A-S., Y.M.K., L.R.J.), Indianapolis, Ind.
Abstract
Abstract
—To investigate the cellular mechanisms for altered Ca
2+
homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca
2+
currents (
I
Ca,L
), whole-cell Ca
2+
transients ([Ca
2+
]
i
), and Ca
2+
sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca
2+
]
i
amplitude (at 0 mV, 1330±62 nmol/L [SHRs] versus 836±48 nmol/L [controls],
P
<0.05) that was not associated with changes in
I
Ca,L
density or kinetics, resting [Ca
2+
]
i
, or Ca
2+
content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca
2+
sparks from SHR cells had larger average amplitudes (173±192 nmol/L [SHRs] versus 109±64 nmol/L [control];
P
<0.05), which was due to redistribution of Ca
2+
sparks to a larger amplitude population. This change in Ca
2+
spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca
2+
-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca
2+
]
i
amplitude, time to relaxation, and average Ca
2+
spark amplitude (“big sparks”). Importantly, big sparks occurred without alteration in the trigger for SR Ca
2+
release (
I
Ca,L
), SR Ca
2+
content, or the expression of several SR Ca
2+
-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca
2+
entry through L-type Ca
2+
channels and the release of Ca
2+
from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca
2+
channels and SR Ca
2+
release channels may underlie the changes in Ca
2+
homeostasis observed in cardiac hypertrophy. Modulation of SR Ca
2+
release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
153 articles.
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