Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus.
Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus.
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DOI：
10.1161/circresaha.109.209767
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发表时间：
2010-04-02
影响因子：
20.1
通讯作者：
Lee HC
中科院分区：
文献类型：
--
作者：
Lu T;Zhang DM;Wang XL;He T;Wang RX;Chai Q;Katusic ZS;Lee HC
The large conductance Ca2+-activated K+ (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor (AT1R) 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. The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels. We found that BK channels, AT1R, Gαq/11, non-phagocytic NAD(P)H oxidases (NOX-1) and c-Src kinases (c-Src) were co-localized in the caveolae of rat arterial smooth muscle cells (SMC) and the integrity of caveolae in SMC was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin (STZ)-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. These results identified a molecular scheme of receptor-enzyme-channel-caveolae microdomain complex, which facilitates the development of vascular BK channel dysfunction in diabetes.
