Affiliation:
1. From the Departments of Physiology (K.R.B., K.K.F., G.K., C.A.W., L.G.M.) and Anatomy and Cell Biology (M.Y.T., S.C.P.), Queen’s University, Kingston Ontario, Canada.
Abstract
Objective—
Oxidative stress (OS) induces smooth muscle cell apoptosis in the atherosclerotic plaque, leading to plaque instability and rupture. Heme oxygenase-1 (HO-1) exerts cytoprotective effects in the vessel wall. Recent evidence suggests that PKB/Akt may modulate HO-1 activity. This study examined the role of Akt in mediating the cytoprotective effects of HO-1 in OS-induced apoptosis of human aortic smooth muscle cells (HASMCs).
Methods and Results—
HASMCs were transduced with retroviral vectors expressing HO-1, Akt, or GFP and exposed to H
2
O
2
. Cell viability was assessed by MTT assay. OS was determined by CM-H2DCFDA fluorescence, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), caspase-3 activity, and Bcl-2/Bad levels. Mitochondrial membrane potential (ΔΨ
m
) was assessed by fluorescence-activated cell sorter (FACS) using JC-1. HO-1 reduced H
2
O
2
-induced OS and apoptosis. Akt knockdown removed the protective effect of HO-1 on ΔΨ
m
during exposure to H
2
O
2
. Conversely, HO-1 knockdown removed the protective effect of Akt on ΔΨ
m
. Inhibition of PI3K-Akt reduced induction of HO-1 protein expression by H
2
O
2
and blocked its anti-apoptotic effects. The Akt-mediated upregulation of HO-1 was dependent on activation of HO-1 promoter by Nrf2.
Conclusion—
HO-1 and Akt exert codependent cytoprotective effects against OS-induced apoptosis in HASMCs. These findings may have implications for the design of novel therapeutic strategies for plaque stabilization.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
94 articles.
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