Alteration in myocardial collagen phenotypes in spontaneously hypertensive rats

60 ALTERATION IN MYOCARDIAL COLLAGEN PHENOTYPES IN SPONTANEOUSLY HYPERTENSIVE RATS. Subha Sen, Ph.D.,D.Sc. Research Division, Cleveland Clinic Foundation, Cleveland, Ohio 44106 An increase in myocardial collagen (both concentration and content) was found in the spontaneously hypertensive rat (SHR) during the established phase of hypertension (24 weeks) (BP= 190t5 mmHG), when compared to age and sex matched Wistar controls (4.62k.26 vs 3.8k.19 mg/g, pc.01; 5.37t.36 mg vs 390+ .2 mg, pc.01). The increase in myocardial collagen is associated with an increase in rate of collagen synthesis (23 ng vs 11.5 ng collagen/100 mg tissue/3 hr, p<.Ol). Prevention of development of hypertension by antihypertensive drugs (amethyldopa) from 3 weeks to 24 weeks prevented the development of myocardial hypertrophy in SHR and normalized the rate of collagen synthesis. The different types of collagen phenotypes in SHR and WKY (6 months old), separated by disc gel electrophoresis, were found to be different. The collagen of WKY rats was composed of u(I), "(III), a2, aA, and aB; whereas in SHR the aA and aB types were not detectable. In contrast, in the young SHR (4 weeks), in absence of hypertension, the collagen pattern was identical to WKY. Antihypertensive therapy with a-methyldopa, which prevented hypertension, normalized the altered collagen pattern of SHR. Results suggest that persistence of hypertension may result in alteration in the formation in collagen component of myocardial protein, and that can be prevented b antihypertensive therapy. (Supported by NIHBL-6835. r

REGULATION OF CARDIAC Ca2++Mg2+-ATPase - A POSSIBLE ROLE FOR PHOSPHOLAMBAN AND CALMODULIN IN THE CALCIUM TRANSPORT MECHANISM. Adil E. Shamoo and Indu S. Ambudkar. Department of Biological Chemistry, University of Maryland School of Medicine,Baltimore, MD 21201. The regulation of Ca2+ -transport of the cardiac sarcoplasmic reticulum (SR) is associated with the phosphorylation of a 22K protein, phospholamban. This protein has been reported to be phosphorylated by both a c-AMP dependent as well as by a Ca 2+calmodulin dependent system. Low concentrations of DOC decrease the c-AMP dependent phosphorylation of the SR. This decrease is accompanied by an 80-90% loss of Ca2+ transporting activity which is not due to change in Ca 2+-permeability. Phosphorylation of the SR membrane before DOC treatment protects the c-AMP dependent phosphor lation of the membrane as Using DOC, we well as the DOC-induced loss of CaS+ uptake. have purified the "native" phospholamban (JBC in press). Removal of calmodulin from these membranes decreases Ca 2+ transport by about 75%, but stimulates the c-AMP dependent phosphorylation by 30%. DOC treatment of calmodulin depleted membranes decreases the c-AMP dependent phosphorylation and the Ca2+ transport to basal levels and also removes the 22K protein from these membranes. Addition of both the c-AMP dependent system and calmodulin restores Ca2+ uptake to 25% of the original control level. The results suggest a specific role of phospholamban in the Ca2+- transporting activity of cardiac sarcoplasmic reticulum. (Supported by the Office of Naval and the Muscular Dystrophy Research, Department of Energy, Association.)