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Inhibition of calcineurin and sarcolemmal Ca2+ influx protects cardiac morphology and ventricular function in K(v)4.2N transgenic mice.

Abstract：

BACKGROUND:Cardiac-targeted expression of truncated K(v)4.2 subunit (K(v)4.2N) reduces transient outward current (I(to)) density, prolongs action potentials (APs), and enhances contractility in 3- to 4-week-old transgenic mice. By 13 to 15 weeks of age, these mice develop severely impaired cardiac function and signs of heart failure. In this study, we examined whether augmented contractility in K(v)4.2N mice results from elevations in intracellular calcium ([Ca2+]i) secondary to AP prolongation and investigated the putative roles of calcineurin activation in heart disease development of K(v)4.2N mice. METHODS AND RESULTS:At 3 to 4 weeks of age, L-type Ca2+ influx and peak [Ca2+]i were significantly elevated in K(v)4.2N myocytes compared with control because of AP prolongation. Cardiac calcineurin activity was also significantly elevated in K(v)4.2N mice by 5 weeks of age relative to controls and increased progressively as heart disease developed. This was associated with activation of protein kinase C (PKC)-alpha and PKC-theta but not PKC-epsilon, as well as increases in beta-myosin heavy chain (beta-MHC) and reductions in sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2a expression. Treatment with either cyclosporin A or verapamil prevented increases in heart weight to body weight ratios, interstitial fibrosis, impaired contractility, PKC activation, and changes in the expression patterns of beta-MHC and SERCA2a. CONCLUSIONS:Our results demonstrate that AP prolongation caused by I(to) reduction results in enhanced Ca2+ cycling and hypercontractility in mice and suggests that elevations in [Ca2+]i via I(Ca,L) and activation of calcineurin play a central role in disease development after I(to) reduction using the K(v)4.2N construct.

journal_name

Circulation

journal_title

Circulation

authors

Sah R,Oudit GY,Nguyen TT,Lim HW,Wickenden AD,Wilson GJ,Molkentin JD,Backx PH

doi

10.1161/01.cir.0000014211.47830.4d

subject

Has Abstract

pub_date

2002-04-16 00:00:00

pages

1850-6

issue

eissn

0009-7322

issn

1524-4539

journal_volume

105

pub_type

杂志文章

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Inhibition of calcineurin and sarcolemmal Ca2+ influx protects cardiac morphology and ventricular function in K(v)4.2N transgenic mice.