Effect of hypercholesterolemia on myocardial function in New Zealand white rabbits

Abstract

Although hypercholesterolemia is a well-known risk factor for atherosclerosis, little is known about the effect of hypercholesterolemia on cardiac contractile function. The objective of this study was to examine the effect of hypercholesterolemia on myocardial contractility. Fifteen New Zealand white rabbits were fed standard chow (control group) and another 15 were fed a cholesterol-enriched diet (HC group) for 12 weeks. The contractile response of ventricular muscle strips was measured in various extracellular calcium concentrations and at different pacing rates. The whole-cell calcium current recording, and mRNA and protein levels of cellular calcium-handling proteins were also analyzed. With 2 mM Ca2+ and stimulation at 3 Hz, the contractile force of HC strips was less than that of the controls (3.63 +/- 0.20 vs. 4.61 +/- 0.50 mN, p < 0.05). The time to peak tension was longer for HC strips (93.3 +/- 2.16 vs. 82.2 +/- 2.81 ms, p < 0.05). The peak L-type calcium inward current density was slightly higher in HC myocytes but did not reach statistical significance (-14.90 +/- 0.94 vs. -12.44 +/- 0.84 pA/pF, p = 0.15). The mRNA level of sarcoplasmic reticulum Ca2+-ATPase (SERCA), normalized to GAPDH, was significantly lower in the HC than that in the control group (2.85 +/- 0.14 vs. 7.67 +/- 0.67, p < 0.05), as was the ryanodine receptor (RyR; 0.42 +/- 0.06 vs. 0.71 +/- 0.13, p < 0.05). The mRNA of the Na+/Ca2+ exchanger (NCX) was statistically higher in the HC group (0.90 +/- 0.12 vs. 0.48 +/- 0.05, p < 0.05). Western blot experiments revealed that protein expression of SERCA in the HC strips decreased, but that of the NCX increased. The protein expression of the dihydropyridine receptor was similar between these two groups. We concluded that hypercholesterolemia results in suppression of the maximal contractile function and in a longer systolic contractile time course. These changes may partially be mediated through a decrease in SERCA and RyR but an increase in NCX expression.