Protection from hypertension phenotype by a mitochondrial division inhibitor in mice infused with angiotensin II

Abstract

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases including hypertension. Mitochondrial fission fusion balance is critical for mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular diseases. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested our hypothesis that inhibition of mitochondrial fission attenuates development of hypertension and associated vascular remodeling. C57BL6 mice were infused with angiotensin II for 2 weeks with or without treatment of mitochondrial fission inhibitor mdivi1. Cultured vascular endothelial cells and adventitial fibroblasts from rat aortas were stimulated with angiotensin II in the presence or absence of mdivi1. In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor mdivi1 significantly inhibited angiotensin II-induced development of hypertension assessed by telemetry. Histological assessment of hearts and aortas demonstrated that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both endothelium and media of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight body weight ratio as well as by echocardiogram. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.