Calcium-dependent signaling in cardiac hypertrophy: Dissection of a pathway.

摘要

Cardiac hypertrophy displays both adaptive and maladaptive features. Accordingly, there is great interest in deciphering disease-specific mechanisms in hopes of affording clinical benefit. Potential targets of therapeutic intervention in cardiac hypertrophy include the L-type Ca2+ channel, the cytoplasmic phosphatase calcineurin, and small GTP-binding proteins such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about interaction---if any---between these important signaling molecules in hypertrophic heart disease. This study examines the molecular interplay among these molecules. In an in vitro model of cardiomyocyte hypertrophy using angiotensin II as a primary stimulus, we find increases in L-type Ca2+ current similar to that observed in a mouse model of pressure-overload hypertrophy. We find that calcineurin activation is dependent upon Ca2+ influx via the L-type channel and that the L-type channel is a downstream target of calcineurin activation, possibly via regulation of the phosphorylation state of channel proteins. In addition, we find that RhoA and Rac1 GTPase signaling occurs either downstream of calcineurin or as a required, parallel pathway. To address the therapeutic relevance of this cascade, we used HMG CoA reductase inhibition as an antihypertrophic strategy in mice and found that "statin" therapy effectively blocked hypertrophy without provoking cardiovascular compromise. Together, these studies decipher a signaling pathway that induces maladaptive hypertrophy and raise the prospect of therapeutic intervention in cardiac hypertrophy by well tolerated, clinically available drugs.