Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against Nitric oxide-mediated nitrative stress in microcirculation in mice

Hiroki Saito, Shigeo Godo, Saori Sato, Akiyo Ito, Yosuke Ikumi, Shuhei Tanaka, Tomoaki Ida, Shigemoto Fujii, Takaaki Akaike, Hiroaki Shimokawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Aims: Nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) play important roles in maintaining cardiovascular homeostasis. We have previously demonstrated that endothelial NO synthase (eNOS) plays diverse roles depending on vessel size, as a NO generating system in conduit arteries and an EDH-mediated system in resistance arteries, for which caveolin-1 (Cav-1) is involved. However, the physiological role of endothelial Cav-1 in microvessels remains to be elucidated. Methods and Results: We newly generated endothelium-specific Cav-1-knockout (eCav-1-KO) mice. eCav-1-KO mice showed loss of endothelial Cav-1/eNOS complex and had cardiac hypertrophy despite normal blood pressure. In eCav-1-KO mice, as compared to wild-type controls, the extent of eNOS phosphorylation at inhibitory Thr495 was significantly reduced in mesenteric arteries and the heart. Isometric tension and Langendorff-perfused heart experiments showed that NO-mediated responses were enhanced, whereas EDH-mediated responses were reduced in coronary microcirculation in eCav-1-KO mice. Immunohistochemistry showed increased level of 8-nitroguanosine 30,50-cyclic monophosphate (8-nitro-cGMP), a marker of nitrative stress, in the heart from eCav-1-KO mice. S-guanylation of cardiac H-Ras in eCav-1-KO mice was also significantly increased compared with wild-type controls. Conclusions: These results suggest that eCav-1 is involved in the protective role of EDH against nitrative stress caused by excessive NO to maintain cardiac microvascular homeostasis.

Original languageEnglish
Pages (from-to)113-126
Number of pages14
JournalJournal of cardiovascular pharmacology
Volume71
Issue number2
DOIs
Publication statusPublished - 2018 Feb 1

Keywords

  • Caveolin-1
  • Endothelium-dependent hyperpolarization
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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