Abstract
The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.
Highlights
Publisher’s Note: MDPI stays neutralActivation of the renin–angiotensin–aldosterone system (RAAS) is known to play an important role in a range of conditions known to increase the risk of developing cardiovascular diseases
Following AngII50 treatment there were no signs of cardiac hypertrophy; using the slow pressor dose (AngII400 ), hypertrophy was evident as increased heart weight and increased cardiac mRNA expression of the gene encoding for the hypertrophic markers natriuretic peptide A(nppa) and natriuretic peptide
We did not find AngII400 to alter the mean arterial pressure (MAP), but there was a modest elevation of the arterial systolic blood pressure (SBP) at two weeks of treatment when compared to baseline (106 ± 3 vs. 94 ± 4 mmHg, respectively, p < 0.05)
Summary
Activation of the renin–angiotensin–aldosterone system (RAAS) is known to play an important role in a range of conditions known to increase the risk of developing cardiovascular diseases. Angiotensin (AngII) induces systemic effects, including arterial vasoconstriction as well as sodium and water retention, which may result in hypertension, increased cardiac workload, and development of heart failure. AngII likely has a key role in cardiac remodelling and the development of cardiac dysfunction, in the absence of hypertension. High doses, >1000 ng/kg/min, typically cause an overt hypertension and hypertrophy [4,5,6], creating severe models of heart disease and possibly with regard to jurisdictional claims in published maps and institutional affiliations
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