on October 25, 2007
Published online before print October 25, 2007, doi: 10.1161/ATVBAHA.107.154294
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Submitted on August 22, 2007
Accepted on October 15, 2007
The Mechanistic Basis for the Disparate Effects of Angiotensin II on Coronary Collateral Growth
Ryan Reed ;
From the Department of Integrative Medical Sciences (C.K., P.R.), Northeastern Ohio Universities College of Medicine, Rootstown; and the Departments of Physiology (B.P.) and Pharmacology (R.R.), Louisiana State University Health Sciences Center, New Orleans.
* To whom correspondence should be addressed. E-mail: procic{at}neoucom.edu.
Objective—We hypothesize that controversial effects of angiotensin II (Ang II) are attributable to its regulation of reactive oxygen species (ROS) and ROS-dependent signaling.
Methods and Results—Coronary collateral growth (CCG) was stimulated in normal (WKY) and syndrome X (JCR) rats by transient/repetitive ischemia (RI). Blood flow was measured in the normal (NZ) and the collateral-dependent (CZ) zone. In WKY, RI increased CZ flow (0.84 mL/min/g), but RI+subpressor Ang II increased it more (1.24 mL/min/g). This was associated with transient p38 and sustained Akt activation. A hypertensive dose of Ang II decreased CZ flow (0.69 mL/min/g), which was associated with sustained p38 and transient Akt activation. AT1R blockade by candesartan abrogated CZ flow in WKY (0.58 mL/min/g), reduced myocardial superoxide, and blocked p38 and Akt activation. RI-induced CZ flow in JCR was significantly decreased compared with WKY (0.12 mL/min/g), associated with a large increase in superoxide and lack of p38 and Akt activation. CZ flow in JCR was partially restored by candesartan (0.45 mL/min/g), accompanied by reduction in superoxide and partial restoration of p38 and Akt activation.
Conclusion—Ang II/AT1R blockade, at least in part, regulates CCG via generating optimal ROS amounts and activating redox-sensitive signaling.
Key words: Angiotensin II • syndrome X • coronary disease • signal transduction
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