Caveolin-3 dependent loss of t-tubular ICa during hypertrophy and heart failure in mice

Abstract

Background

Previous work has shown redistribution of L-type Ca current (I_Ca) from the t-tubules to the surface membrane of rat ventricular myocytes following myocardial infarction. However, whether this occurs in all species and in response to other insults, the relationship of this redistribution to the severity of the pathology, and the underlying mechanism, are unknown. We have therefore investigated the response of mouse hearts and myocytes to pressure overload induced by transverse aortic constriction (TAC).

Methods

Male C57BL/6 mice underwent TAC or equivalent Sham operation 8 weeks before use. I_Ca and calcium transients were measured in isolated myocytes, and Caveolin-3 (Cav-3) Junctophillin-2 (JPH-2) and Bridging Integrator-1 (BIN-1) expression determined. C3SD peptide was used to disrupt Cav-3 binding to its protein partners.

Results

Some animals showed cardiac hypertrophy in response to TAC with little evidence of heart failure, whereas others showed greater hypertrophy and pulmonary congestion. These graded changes were accompanied by graded cellular hypertrophy, t-tubule disruption, decreased expression of JPH-2 and Cav-3, and decreased t-tubular I_Ca density, with no change at the cell surface, and graded impairment of Ca release at t-tubules. C3SD decreased I_Ca density in control, but not in TAC myocytes.

Conclusions

These data suggest that the graded changes in cardiac function and size that occur in response to TAC are paralleled by graded changes in cell structure and function, which will contribute to the impaired function observed in vivo. They also suggest that loss of t-tubular I_Ca is due to loss of Cav-3 dependent stimulation of I_Ca.

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