(Hypertension. 2000;36:851.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Docosahexaenoic Acid, a Peroxisome Proliferator–Activated Receptor-
Ligand, Induces Apoptosis in Vascular Smooth Muscle Cells by Stimulation of p38 Mitogen-Activated Protein Kinase
From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca
Abstract—Omega-3 fatty acids (n-3
FAs) have been shown to exert a blood pressure–lowering effect in
hypertension, possibly in part by influencing vascular structure. We
previously demonstrated that n-3 FAs induce vascular smooth muscle cell
(VSMC) apoptosis, which could exert an effect on the structure
of blood vessels. In the present study, we investigated signaling
pathways through which n-3 FAs mediate apoptosis in VSMCs.
Cultured mesenteric VSMCs from Sprague-Dawley rats were stimulated with
docosahexaenoic acid (DHA), a representative n-3 FAs.
Morphological changes in apoptosis and DNA fragmentation were
examined with phase-contrast microscopy and fluorescence
microscopy with Hoechst 33342 staining. To clarify possible pathways of
apoptosis, we evaluated the expression of
phosphorylated p38 mitogen-activated protein
kinases, bax, bcl-2, cytochrome c, and peroxisome
proliferator-activated receptor-
(PPAR-) with Western
blot analysis. DHA treatment induced cell shrinkage, cell
membrane blebbing, and apoptotic bodies in VSMCs. DHA
time-dependently activated p38 mitogen-activated
protein kinases, bax, PPAR-, and cytochrome c, with
maximal effects obtained after 5 and 30 minutes and 1 and 3 hours,
respectively. SB-203580 and SB-202190, selective p38
inhibitors, reduced DHA-elicited apoptosis and
expression of PPAR- but had no effect on the expression of bax or
cytochrome c. The present results indicate that DHA
induces apoptosis in VSMCs through 
2 distinct mechanisms: (1)
a p38-dependent pathway that regulates PPAR- and (2) a
p38-independent pathway via dissipation of mitochondrial membrane
potential and cytochrome c release. The death-signaling
pathway stimulated by DHA may involve an integration of these multiple
pathways. By triggering VSMC apoptosis, DHA may play a
pathophysiological role in vascular remodeling in
cardiovascular disease.
Key Words: fatty acids • docosahexaenoic acid • apoptosis • cells • muscle, smooth, vascular • protein kinases
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