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

Abstract

New Findings What is the central question of this study? Heart failure is associated with redistribution of L‐type Ca2+ current (I Ca) away from the t‐tubule membrane to the surface membrane of cardiac ventricular myocytes. However, the underlying mechanism and its dependence on severity of pathology (hypertrophy versus failure) are unclear. What is the main finding and its importance? Increasing severity of response to transverse aortic constriction, from hypertrophy to failure, was accompanied by graded loss of t‐tubular I Ca and loss of regulation of I Ca by caveolin 3. Thus, the pathological loss of t‐tubular I Ca, which contributes to impaired excitation–contraction coupling and thereby cardiac function in vivo, appears to be attributable to loss of caveolin 3‐dependent stimulation of t‐tubular I Ca. Previous work has shown redistribution of L‐type Ca2+ current (I Ca) from the t‐tubules to the surface membrane of rat ventricular myocytes after 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). Male C57BL/6 mice underwent TAC or equivalent sham operation 8 weeks before use. I Ca and Ca2+ transients were measured in isolated myocytes, and expression of caveolin 3 (Cav3), junctophilin 2 (Jph2) and bridging integrator 1 (Bin1) was determined. C3SD peptide was used to disrupt Cav3 binding to its protein partners. 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 Jph2 and Cav3, and decreased t‐tubular I Ca density, with no change at the cell surface, and graded impairment of Ca2+ release at t‐tubules. C3SD decreased I Ca density in control but not in TAC myocytes. 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 attributable to loss of Cav3‐dependent stimulation of I Ca.