A Ca(2+)-dependent transgenic model of cardiac hypertrophy: A role for protein kinase Calpha.
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.


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 Calpha 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 Ca(2+) through the calcium channel elevated protein kinase Calpha before the development of hypertrophy, suggesting that protein kinase Calpha plays an important role in triggering hypertrophy.
Muth
J N
JN
Institute of Molecular Pharmacology and Biophysics, Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0828, USA.
Bodi
I
I
Lewis
W
W
Varadi
G
G
Schwartz
A
A
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression / Q000235:genetics; D017136:Ion Transport / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D015398:Signal Transduction / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
D020746:Calcium Channels, L-Type; D007527:Isoenzymes; C497256:Prkce protein, mouse; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D002118:Calcium