期刊
CIRCULATION JOURNAL
卷 76, 期 7, 页码 1768-1779出版社
JAPANESE CIRCULATION SOC
DOI: 10.1253/circj.CJ-12-0197
关键词
Endothelial nitric oxide synthase; Endothelium-derived hyperpolarizing factor; Microveesels; Nitric oxide
资金
- Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan
- Grants-in-Aid for Scientific Research [20117009, 22390154, 23659071] Funding Source: KAKEN
Background: Endothelium-derived relaxing factors play an important role in cardiovascular homeostasis. Among them, endothelium-derived hyperpolarizing factor (EDHF) is important especially in microcirculation. It has previously been demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans and that endothelial nitric oxide synthase (eNOS) plays diverse roles as a nitric oxide (NO) generating system in conduit arteries and as an EDHF/H2O2 generating system in microvessels. As compared with NO-mediated responses, those by EDHF are resistant to atherosclerosis, contributing to the maintenance of cardiovascular homeostasis. The aim of this study is to elucidate the molecular mechanisms for enhanced EDHF-mediated responses in microvessels. Methods and Results: This study used male wild-type mice and caveolin-1-deficient mice (caveolin-1(-/-) mice). In the endothelium, eNOS was functionally suppressed in mesenteric arteries (microvessels) compared with the aorta (conduit arteries), for which Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKK beta) and caveolin-1(-/-) are involved, as EDHF-mediated responses were inhibited by STO-609 (an inhibitor of CaMKK beta) and in caveolin-1(-/-) mice, respectively. In vascular smooth muscle, relaxation responses to H2O2 were enhanced through a protein kinase G1 alpha (PKG1 alpha)-mediated mechanism in mesenteric arteries compared with the aorta, as they were inhibited by Rp-8-Br-cGMPS (an inhibitor of PKG1 alpha). Conclusions: These results indicate that CaMKK beta, caveolin-1, and PKG1 alpha are substantially involved in the mechanisms for the enhanced EDHF-mediated responses in microvessels in mice. (Circ J 2012; 76: 1768-1779)
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