Abstract
Phospholamban is the regulator of the cardiac sarcoplasmic reticulum (SR) Ca2+-ATPase activity and an important modulator of basal contractility in the heart. To determine whether all the SR Ca2+-ATPase enzymes are subject to regulation by phospholamban in vivo, transgenic mice were generated which overexpressed phospholamban in the heart, driven by the cardiac-specific α- myosin heavy chain promoter. Quantitative immunoblotting revealed a twofold increase in the phospholamban protein levels in transgenic hearts compared to wild type littermate hearts. The transgenic mice showed no phenotypic alterations and no changes in heart/body weight, heart/lung weight, and cardiomyocyte size. Isolated unloaded cardiac myocytes from transgenic mice exhibited diminished shortening fraction (63%) and decreased rates of shortening (64%) and relengthening (55%) compared to wild type (100%) cardiomyocytes. The decreases in contractile parameters of transgenic cardiomyocytes reflected decreases in the amplitude (83%) of the Ca2+ signal and prolongation (131%) in the time for decay of the Ca2+ signal, which was associated with a decrease in the apparent affinity of the SR Ca2+-ATPase for Ca2+ (56%), compared to wild type (100%) cardiomyocytes. In vivo analysis of left ventricular systolic function using M mode and pulsed-wave Doppler echocardiography revealed decreases in fractional shortening (79%) and the normalized mean velocity of circumferential shortening (67%) in transgenic mice compared to wild type (100%) mice. The differences in contractile parameters and Ca2+ kinetics in transgenic cardiomyocytes and the depressed left ventricular systolic function in transgenic mice were abolished upon isoproterenol stimulation. These findings indicate that a fraction of the Ca2+-ATPases in native SR is not under regulation by phospholamban. Expression of additional phospholamban molecules results in: (a) inhibition of SR Ca2+ transport; (b) decreases in systolic Ca2+ levels and contractile parameters in ventricular myocytes; and (c) depression of basal left ventricular systolic function in vivo.
Original language | English |
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Pages (from-to) | 533-539 |
Number of pages | 7 |
Journal | Journal of Clinical Investigation |
Volume | 97 |
Issue number | 2 |
DOIs | |
State | Published - Jan 15 1996 |
Keywords
- cardiomyocyte
- left ventricular function
- overexpression
- phospholamban
- transgenic