A Ca ²⁺ -Dependent Transgenic Model of Cardiac Hypertrophy

<jats:p> <jats:italic>Background</jats:italic> —Calcium imbalances have been implicated as an underlying mechanism of human cardiac dysfunction. The voltage-dependent calcium channel plays a critical role in calcium regulation in the heart. Thus, aberrant calcium signaling arising from this channel could initiate the calcium imbalances observed in heart failure. In the present study, we used a transgenic mouse with an increased number of L-type calcium channels to identify the role of an increased, sustained ingress of calcium as an initiator of hypertrophy. </jats:p> <jats:p> <jats:italic>Methods and Results</jats:italic> —Whole-heart histology and electrophysiology in isolated cardiomyocytes identified calcium-channel overexpression in the hearts of transgenic mice. Calcium-channel density was increased in 2-, 4-, and 8-month-old transgenic cardiomyocytes. Ventricular fibrosis, damage, and remodeling became more pronounced as the transgenic mice aged. Apoptosis was also present in transgenic hearts at 8 months of age. Increased protein kinase Cα activation was elevated before the development of hypertrophy and failure. </jats:p> <jats:p> <jats:italic>Conclusions</jats:italic> —Transgenic mice developed hypertrophy and severe cardiomyopathy as a function of age, thus confirming that changes in channel density are sufficient to induce disease. The small, sustained increase in the ingress of Ca <jats:sup>2+</jats:sup> through the calcium channel elevated protein kinase Cα before the development of hypertrophy, suggesting that protein kinase Cα plays an important role in triggering hypertrophy. </jats:p>