A Ca2+-Dependent Transgenic Model of Cardiac Hypertrophy: A Role for Protein Kinase Cα
JN Muth, I Bodi, W Lewis, G Varadi, A Schwartz - Circulation, 2001 - Am Heart Assoc
JN Muth, I Bodi, W Lewis, G Varadi, A Schwartz
Circulation, 2001•Am Heart AssocBackground—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. Methods and …
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. Methods and …
Background—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.
Methods and Results—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.
Conclusions—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 Ca2+ 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.
Am Heart Assoc