Dilated Cardiomyopathy with Increased SR Ca2+ Loading Preceded by a Hypercontractile State and Diastolic Failure in the α1CTG Mouse

Su Wang,Ying-Ying Zhou,Nanette H Bishopric,Bruce Ziman,Marta Rubio,Ilona Bodi,Edward G Lakatta,Arnold Schwartz,Karen D'Souza,Pieter H Reitsma

doi:10.1371/journal.pone.0004133

Su Wang, Ying-Ying Zhou + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0004133

Copy DOI

Abstract

Mice over-expressing the α1−subunit (pore) of the L-type Ca2+ channel (α1CTG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8–11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2–4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models.

Highlights

Much evidence has accumulated since the first cytosolic Ca2+ transient measurements in cardiac muscle from heart failure (HF) patients [1] to support a role for alterations in myocyte ‘‘Ca2+ handling’’ in the pathophysiology of HF
Body weight did not differ between NTG and non-failing advanced hypertrophic stage (NFTG) but body weight increased by 15% in failing a1CTG (FTG), likely as a result of fluid accumulation (Figure 1B)
The average myocyte size, estimated from cell capacitance, reflected the relative heart mass. It increased by 25% in NFTG vs NTG, and in FTG further increased by 29%

Summary

Introduction

Much evidence has accumulated since the first cytosolic Ca2+ transient measurements in cardiac muscle from heart failure (HF) patients [1] to support a role for alterations in myocyte ‘‘Ca2+ handling’’ in the pathophysiology of HF. Multiple alterations in various aspects of myocyte excitation-contraction coupling have been observed in HF, the central mechanism of the reduced Ca2+ transient amplitude has been emphasized and has been attributed to a reduction of sarcoplasmic reticulum (SR) Ca2+ content [1,2,3,4,5,6,7]. Longitudinal assessment of cardiac structure and function in a novel transgenic mouse that over expresses the a1C-subunit of the L-type Ca2+ channel (a1CTG) indicates that like droves of other ‘‘boutique mice’’ (Table S1), this mouse, develops cardiac hypertrophy, during which adaptive Ca2+ regulatory mechanisms are mobilized. The remarkable orchestration among cardiomyocyte Ca2+ regulatory proteins in this model at 4months (mo) is instructive because it provides clues with respect to coordinated, adaptive remodeling of Ca2+ regulation to maintain a normal SR Ca2+ load at 4 mo of age [4]. An overexpression of NCX protein, which enhances Ca2+ efflux to balance the enhanced Ca2+ influx via the overexpressed L-type Ca2+ channel prevents excess cytosolic calcium loading [4]

Methods

Results

Conclusion