Cardiac hypertrophy leads to coronary microvascular dysfunction and enhanced endothelin‐1/Rho‐kinase signaling in mice with transverse aortic coarctation (676.1)

Abstract

Hypertensive cardiac hypertrophy induced by transverse aortic coarctation (TAC) has been reported to reduce coronary flow reserve in mice, but its impact on oxygen delivery and microvascular function remains unknown. In the present study, we found that induction of TAC in mice for 3‐4 weeks increased heart‐to‐body weight ratio by 55% and decreased cardiac fractional shortening and left coronary arterial blood velocity (LCABV) by 51% and 21%, respectively. The myocardial lactate level was 43% higher in TAC than sham control mice. Isoproterenol (5 µg/g, i.p.) increased heart rate by 20% but the increased LCABV (23%) was observed only in the sham mice. In TAC mice, the superoxide levels in myocardium and coronary arterioles were increased by 1.7‐ and 2.3‐fold, respectively, and the myocardial endothelin‐1 (ET‐1) was increased by 59%. The endothelium‐dependent, nitric oxide (NO)‐mediated vasodilations to acetylcholine and adenosine, but not endothelium‐independent vasodilations to NO donor sodium nitroprusside, were impaired in TAC mice. The Rho kinase (ROCK)‐dependent vasoconstriction to ET‐1 was enhanced and the expressions of ROCK‐1 and ‐2 were increased in coronary arterioles of TAC mice. We conclude that myocardial pressure overload leads to cardiac deficiency, coronary microvascular dysfunction and ischemia possibly due to oxidative stress, elevated ET‐1/ROCK signaling and compromised NO function.Grant Funding Source: Supported by Kruse Endowed Research Fund from Baylor Scott & White Healthcare