Mitochondrial fission inhibition protects against hypertension induced by angiotensin II

Kyle J. Preston, Tatsuo Kawai, Keiichi Torimoto, Ryohei Kuroda, Yuki Nakayama, Tomoko Akiyama, Yayoi Kimura, Rosario Scalia, Michael V. Autieri, Victor Rizzo, Tomoki Hashimoto, Patrick Osei-Owusu, Satoru Eguchi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Mitochondrial dysfunction has been implicated in various types of cardiovascular disease including hypertension. Mitochondrial fission fusion balance is critical to mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular disease. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested the hypothesis that inhibition of mitochondrial fission attenuates the development of hypertension and associated vascular remodeling. 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 radiotelemetry. Histological assessment of hearts and aortas showed 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 the endothelial and medial layers of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight-to-body weight ratio as well as by echocardiography. In ex vivo experiments, mdivi1 inhibited vasoconstriction and abolished the enhanced vascular reactivity by angiotensin II in small mesenteric arteries. 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. (Figure presented.).

Original languageEnglish
Pages (from-to)1338-1349
Number of pages12
JournalHypertension Research
Volume47
Issue number5
DOIs
StatePublished - May 2024

Keywords

  • Angiotensin II
  • Fibrosis
  • Hypertension
  • Mitochondria
  • Proteomics
  • Mice, Inbred C57BL
  • Hypertension/chemically induced
  • Male
  • Angiotensin II/pharmacology
  • Animals
  • Mitochondrial Dynamics/drug effects
  • Blood Pressure/drug effects
  • Vascular Remodeling/drug effects
  • Mice
  • Quinazolinones/pharmacology

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