Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts

Objective: Both aging and myocardial ischemia are associated with alterations of calcium-regulating proteins. We investigated the effects of graded levels ai low-flow ischemia on myocardial function and on SR Ca2+-ATPase (SERCA2): Na+-Ca2+ exchanger (NCx) and ryanodine receptor (RyR2), at mRNA and protein levels in both adult and senescent myocardium. Methods: Isolated hearts from 4 and 24 month old (mo) rats were retrogradely perfused during 180 min at 100% (100% CF, n = 11 and (n = 11 respectively), 30% (30% CF, n = 10 and n = 12) or 15% (15% CF, n = 13 and n = 8) of their initial coronary flow, and active tension and coronary resistance tin % of their baseline value) were recorded. After 180 min of perfusion, NCx, RyR2 and SERCA2 mRNAs (in % of age-matched 100% CF group value) and protein levels were quantitated in the left ventricles by slot blot and Western blot analysis, respectively. Results: In 24 mo hearts, low-flow ischemia induced a greater fall in active tension (-65 +/- 7% vs. -40 +/- 4% in 4 mo 30% CF, p < 0.01 and -82 +/- 2% vs. -60 +/- 5% in 4 mo 15% CF groups, p < 0.05 after 15 min of ischemia) and a greater increase in coronary resistance (+ 357 +/- 44% vs. + 196 +/- 39% in 4 mo 30% CF, p < 0.05 and + 807 +/- 158% vs, + 292 +/- 61% in 4 mo 15% CF groups, p < 0.001 after 15 min of ischemia). An increased accumulation of SERCA2 (+ 36%) and NCx (+ 46%) transcripts, but not RyR2, already occurred in 24 mo 30% CF group while the 3 transcripts accumulated in 24 mo 15% CF group. In 4 mo rats SERCA2 (+ 26%), NCx (+ 35%) and RyR2 (+ 81%) mRNA levels only increased in the 15% CF group. Corresponding calcium-regulating protein levels were unaltered whatever the degree of flow reduction in both 4 mo and 24 mo hearts. Conclusion: Low-flow ischemia does not induce calcium-regulating protein loss in both adult and senescent hearts. The increase in mRNAs coding for calcium-handling proteins and the impairment of myocardial function which occur at a lesser degree of coronary flow reduction in senescent hearts, indicate a higher vulnerability to low-flow ischemia during aging. (C) 1998 Elsevier Science B.V.