(Hypertension. 1999;34:976-982.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells
From the Experimental Hypertension Laboratory, MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal and Université de Montréal, Montreal, Quebec, Canada H2W 1R7.
Correspondence to Rhian M. Touyz, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail touyz{at}ircm.umontreal.ca
Abstract—Intracellular signaling events that mediate the long-term effects of Ang II in vascular smooth muscle cells are unclear, but oxidative stress may play an important role. This study examined the ability of Ang II to generate reactive oxygen species and investigated the putative role of phospholipase D (PLD)–dependent signaling pathways for its production in human vascular smooth muscle cells. In addition, we assessed whether redox-sensitive pathways influence Ang II–stimulated cell growth. Primary and low-passage cells (passages 1 to 4) derived from resistance arteries of subcutaneous gluteal biopsies from healthy subjects were studied. Oxidative stress was measured with the fluorescent probe 5-(and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) (8 µmol/L), and the role of PLD was assessed with the PLD inhibitor D-erythro-sphingosine, dihydro (sphinganine) (10 µmol/L). To determine whether NADH/NADPH oxidase contributes to production of reactive oxygen species, Ang II–stimulated cells were pretreated with the specific flavoprotein inhibitor diphenylene iodinium (DPI) (10 µmol/L). DNA and protein synthesis were determined by [3H]thymidine and [3H]leucine incorporation, respectively. Ang II increased CM-H2DCFDA fluorescence, and this was inhibited by catalase (350 U/mL), indicating that the fluorescence signal was derived predominantly from H2O2. Ang II dose-dependently increased H2O2 production (Emax=57.6±1.7 nmol/L, pD2=7.7±0.06) and PLD activation (Emax=207±3.3% of control, pD2=7.7±0.5). H2O2 effects were evident within 1 hour, and maximal PLD activation occurred within 40 minutes after stimulation. DPI inhibited (P<0.01) Ang II–stimulated responses. PLD inhibition significantly attenuated (P<0.05) Ang II–elicited H2O2 production (Emax=29±5 nmol/L). DPI and sphinganine inhibited Ang II–induced DNA and protein synthesis. These data indicate that in vascular smooth muscle cells from human peripheral resistance arteries, Ang II increases H2O2 generation via PLD-dependent, NADH/NADPH oxidase–sensitive pathways. These cascades may function as second messengers in long-term Ang II–mediated growth-signaling events.
Key Words: oxidative stress • superoxide anions • intracellular signaling • vascular hypertrophy
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