TY - JOUR
T1 - Regulation of coronary arterial bk channels by caveolae-mediated angiotensin II signaling in diabetes mellitus
AU - Lu, Tong
AU - Zhang, Dai Min
AU - Wang, Xiao Li
AU - He, Tongrong
AU - Wang, Ru Xing
AU - Chai, Qiang
AU - Katusic, Zvonimir S.
AU - Lee, Hon Chi
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - Angiotensin II
KW - BK channel
KW - Caveolin-1
KW - Coronary smooth muscle cells
KW - Reactive oxygen species
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U2 - 10.1161/CIRCRESAHA.109.209767
DO - 10.1161/CIRCRESAHA.109.209767
M3 - Article
C2 - 20167931
AN - SCOPUS:77951017344
SN - 0009-7330
VL - 106
SP - 1164
EP - 1173
JO - Circulation research
JF - Circulation research
IS - 6
ER -