Regulation of coronary arterial bk channels by caveolae-mediated angiotensin II signaling in diabetes mellitus

Tong Lu, Dai Min Zhang, Xiao Li Wang, Tongrong He, Ru Xing Wang, Qiang Chai, Zvonimir S. Katusic, Hon Chi Lee

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

RATIONALE: The large conductance Ca2+-activated K+ (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined. OBJECTIVES: The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels. METHODS AND RESULTS: Using patch clamp techniques and molecular biological approaches, we found that BK channels, Ang II type 1 receptor, Gαq/11 (G protein q/11 α subunit), nonphagocytic NAD(P)H oxidases (NOX-1), and c-Src kinases (c-Src) were colocalized in the caveolae of rat arterial smooth muscle cells and the integrity of caveolae in smooth muscle cells was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes. CONCLUSIONS: These results identified a molecular scheme of receptor/enzyme/channel/caveolae microdomain complex that facilitates the development of vascular BK channel dysfunction in diabetes.

Original languageEnglish (US)
Pages (from-to)1164-1173
Number of pages10
JournalCirculation research
Volume106
Issue number6
DOIs
StatePublished - Apr 1 2010

Keywords

  • Angiotensin II
  • BK channel
  • Caveolin-1
  • Coronary smooth muscle cells
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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