Cocaine produces cardiac hypertrophy by protein kinase C dependent mechanisms.

Background: Chronic cocaine users can have as much as a 69% increase in left ventricular muscle mass without associated increases in arterial blood pressure, heart rate, renin, aldosterone, or cortisol. We determined whether cocaine directly increases cardiomyocyte protein content and whether protein kinase C is important in this process.

Methods And Results: Adult rat cardiomyocytes were isolated and grown in cultures. In Series I experiments, cocaine, 10(-8) to 10(-6) M, or vehicle, in the absence or presence of phentolamine or metoprolol, was added to each culture and the cells were subsequently harvested. In Series II, cocaine, 10(-6) M, cocaine, 10(-6) M, plus bisindolylmaleimide, 10(-6) M, a protein kinase C inhibitor, or vehicle were added to each culture and the cells subsequently harvested. We determined the total protein content, the content of alpha-myosin and fetal beta-myosin heavy-chain protein, and the presence of protein kinase C isoforms in the cardiomyocyte soluble and particulate fractions. Protein kinase C translocation from the soluble to particulate fraction is indicative of activation. In Series III, we determined the cocaine effects on ERK, SAPK/JNK, and p38. In Series I, cocaine, 10(-8) to 10(-6) M, dose-dependently increased myocyte protein content by as much as 28%+/-2% (P<.001) and fetal beta-myosin heavy-chain protein content by 80%+/-2% (P<.001). Neither phentolamine nor metoprolol inhibited this process. In Series II, we determined that ventricular myocytes contain alpha (alpha), beta (beta), delta (delta), epsilon (epsilon), and zeta (zeta) protein kinase C isoforms. Cocaine, 10(-6) M, caused a 45+/-5% increase (P<.001) in protein kinase Calpha in the particulate fraction. The addition of a protein kinase C inhibitor to the myocyte cultures prevented the cocaine-induced translocation of protein kinase Calpha and limited the increase in beta-myosin heavy-chain protein content by >75% (P<.001). However, cocaine did not increase the phosphorylation of ERK, SAPK/JNK or p38 in Series III.

Conclusions: Cocaine increases adult cardiomyocyte protein content by protein kinase Calpha-dependent mechanisms, and this process can contribute to the cardiac hypertrophy and cardiomyopathy that results from chronic cocaine use.