Cardiac-specific overexpression of caveolin-3 preserves t-tubular ICa during heart failure in mice.

Cherrie H T Kong,Hemal H Patel,Mark B Cannell,Andrew F James,Judy J Watson,Simon M Bryant,Clive H Orchard,David M Roth

doi:10.1113/ep087304

Abstract

New Findings What is the central question of this study? What is the cellular basis of the protection conferred on the heart by overexpression of caveolin‐3 (Cav‐3 OE) against many of the features of heart failure normally observed in vivo? What is the main finding and its importance? Cav‐3 overexpression has little effect in normal ventricular myocytes but reduces cellular hypertrophy and preserves t‐tubular I Ca, but not local t‐tubular Ca2+ release, in heart failure induced by pressure overload in mice. Thus Cav‐3 overexpression provides specific but limited protection following induction of heart failure, although other factors disrupt Ca2+ release. Caveolin‐3 (Cav‐3) is an 18 kDa protein that has been implicated in t‐tubule formation and function in cardiac ventricular myocytes. During cardiac hypertrophy and failure, Cav‐3 expression decreases, t‐tubule structure is disrupted and excitation–contraction coupling (ECC) is impaired. Previous work has suggested that Cav‐3 overexpression (OE) is cardio‐protective, but the effect of Cav‐3 OE on these cellular changes is unknown. We therefore investigated whether Cav‐3 OE in mice is protective against the cellular effects of pressure overload induced by 8 weeks’ transverse aortic constriction (TAC). Cav‐3 OE mice developed cardiac dilatation, decreased stroke volume and ejection fraction, and hypertrophy and pulmonary congestion in response to TAC. These changes were accompanied by cellular hypertrophy, a decrease in t‐tubule regularity and density, and impaired local Ca2+ release at the t‐tubules. However, the extent of cardiac and cellular hypertrophy was reduced in Cav‐3 OE compared to WT mice, and t‐tubular Ca2+ current (I Ca) density was maintained. These data suggest that Cav‐3 OE helps prevent hypertrophy and loss of t‐tubular I Ca following TAC, but that other factors disrupt local Ca2+ release.

Highlights

Excitation–contraction coupling (ECC) in cardiac myocytes is initiated by the action potential, which activates sarcolemmal L-type Ca2+ channels (LTCCs)
Since t-tubule structure was altered following transverse aortic constriction (TAC) in Cav-3 OE myocytes, we investigated the expression of JPH-2, which has been implicated in t-tubule and dyad formation
To determine whether the preservation of t-tubular ICa in Cav-3 OE myocytes helps to maintain Ca2+ release, we investigated the latency and heterogeneity of Ca2+ release along a single t-tubule from the time of membrane depolarization (Figure 5a), which showed that Cav-3 OE had no significant effect on latency, nor did it affect the increase in latency of both the initial and maximum rate of rise of Ca2+ observed following TAC (Figure 5b, top), suggesting that TAC-induced impairment of local Ca2+ release is unaffected by Cav-3 OE

Summary

Introduction

Excitation–contraction coupling (ECC) in cardiac myocytes is initiated by the action potential, which activates sarcolemmal L-type Ca2+ channels (LTCCs). The consequent Ca2+ influx (ICa) triggers Ca2+ release from adjacent sarcoplasmic reticulum (SR) via Ca2+ release channels (ryanodine receptors; RyRs). This Ca2+-induced Ca2+ release (Fabiato, 1985) produces local increases of cytosolic [Ca2+] (‘Ca2+ sparks’; Cheng, Lederer, & Cannell, 1993) that summate to form the cytosolic Ca2+ transient, leading to contraction. & Lederer, 1994; Kawai, Hussain, & Orchard, 1999; Lindner, 1957). This arrangement achieves near-synchronous Ca2+ release (Cheng, Cannell, & Lederer, 1994), and contraction, throughout the cell. Relaxation occurs as cytosolic [Ca2+] decreases, mainly due to reuptake into the SR, and by removal from the cell via Na+–Ca2+ exchange (Negretti, O'Neill, & Eisner, 1993)

Methods

Results

Discussion

Conclusion