LIPID MODIFICATION OF THE SENESCENT HEART
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Aging is associated with impaired cardiac relaxation. This impairment in diastolic function contributes to the exponential increase in heart failure among the elderly and may limit exercise capacity in normal elders. Although the mechanisms responsible for the age-related impairment in cardiac relaxation are incompletely understood, decreased sequestration of calcium by the sarcoplasmic reticulum (SR) away from the contractile apparatus has been implicated as a major cause. We have shown, in both young and old rats, that a corn oil supplemented diet produces significant increases in cardiac SR calcium uptake without altering the CaATPase protein content of the SR and that this change correlates with improved cardiac diastolic function. Our overall hypothesis is that the phospholipid remodeling induced in the cardiac SR by the diet modification enhances the mobility of an integral membrane protein, the SR CaATPase, thus allowing more rapid cycling through the ATP hydrolytic cycle and increased calcium uptake. We hypothesize that corn-oil dietary supplementation will result in (1) enhanced cardiac function of left-ventricular papillary muscles from old animals; (2) increased SR CaATPase protein mobility in isolated rat cardiac SR, which is a function of an increased fluidity of the lipids intimately associated with the CaATPase protein; and (3) that the increase in cardiac SR calcium uptake will be caused, not from global metabolic effects of the diet, but by the direct effect of the lipid modification of the cardiac myocyte. To test these hypotheses we will determine isometric cardiac function, using isolated left-ventricular papillary muscles from adult and old rats fed control and experimental diets, and assess SR function in situ; determine the mobility of labeled SR CaATPase protein and lipid, using fluorescence and phosphorescence techniques using cardiac SR vesicles isolated from young and old rats fed control and experimental diets; and examine the direct effects on SR- dependent calcium uptake by rat cardiac myocyte after culture in specific fatty acid-supplemented media. These studies may provide a therapeutic approach to cardiac diastolic dysfunction in the aged, a problem for which no therapeutic agents exist at this time. The insight into the mechanism by which membrane-lipid modification increases the calcium uptake of cardiac SR may be generalizable to other integral membrane ion pumps.
