Manganese superoxide dismutase inhibits neointima formation through attenuation of migration and proliferation of vascular smooth muscle cells

doi:10.1016/j.freeradbiomed.2011.10.442

Free Radical Biology and Medicine

Volume 52, Issue 1, 1 January 2012, Pages 173-181

https://doi.org/10.1016/j.freeradbiomed.2011.10.442 Get rights and content

Abstract

Superoxide anion is elevated during neointima development and is essential for neointimal vascular smooth muscle cell (VSMC) proliferation. However, little is known about the role of manganese superoxide dismutase (MnSOD, SOD2) in the neointima formation following vascular injury. SOD2 in the mitochondria plays an important role in cellular defense against oxidative damage. Because of its subcellular localization, SOD2 is considered the first line of defense against oxidative stress and plays a central role in metabolizing superoxide. Because mitochondria are the most important sources of superoxide anion, we speculated that SOD2 may have therapeutic benefits in preventing vascular remodeling. In this study, we used a rat carotid artery balloon-injury model and an adenoviral gene delivery approach to test the hypothesis that SOD2 suppresses vascular lesion formation. SOD2 was activated along with the progression of neointima formation in balloon-injured rat carotid arteries. Depletion of SOD2 by RNA interference markedly promoted the lesion formation, whereas SOD2 overexpression suppressed the injury-induced neointima formation via attenuation of migration and proliferation of VSMCs. SOD2 exerts its inhibitory effect on VSMC migration induced by angiotensin II by scavenging superoxide anion and suppressing the phosphorylation of Akt. Our data indicate that SOD2 is a negative modulator of vascular lesion formation after injury. Therefore, SOD2 augmentation may be a promising therapeutic strategy for the prevention of lesion formation in proliferative vascular diseases such as restenosis.

Graphical abstract

Highlights

► SOD2 was activated during neointima formation in balloon-injured carotid arteries. ► SOD2 knockdown promoted while SOD2 overexpression suppressed the neointima formation. ► SOD2 inhibited vascular smooth muscle cell (SMC) migration and proliferation. ► SOD2 inhibited SMC migration via scavenging O₂.^- and suppressing PI3/Akt signaling. ► SOD2 is a negative modulator of vascular lesion formation following injury.

Section snippets

Animals

Male Sprague–Dawley rats weighing 450–500 g were purchased from Harlan. All rats were housed under conventional conditions in animal care facilities. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals. All animal experiments were approved by the Animal Care and Use Committee of the University of Georgia.

Cell culture

VSMCs were isolated by autogrowth of

SOD2 expression is increased in carotid artery after balloon withdrawal injury

To ascertain the role of SOD2 in vascular remodeling, we first generated a rat carotid artery balloon-injury model and compared SOD2 expression levels in injured arteries with uninjured (control) vessels. Normal and injured arteries at 1, 3, 7, and 14 days after surgery were harvested and paraffin-embedded. Vessel sections were stained with H&E (Fig. 1A, top). Neointima was first observed at 3 days and progressively increased at 7 and 14 days after the injury, as reported previously [16].

Discussion

SOD2 is a unique form of superoxide dismutase containing manganese and is located in the mitochondria, the most important sources of O₂^•− [15]. Because of its special subcellular localization, SOD2 is considered to be the first line of defense against oxidative stress and plays a central role in metabolizing superoxide [11]. O₂^•− plays an important role in neointima formation and is essential for neointimal VSMC proliferation [5]. To gain an insight into the role of SOD2 in neointima formation

Acknowledgment

This work was supported by grants from the National Institutes of Health (HL093429 and HL107526 to Dr. Chen).

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Original ContributionManganese superoxide dismutase inhibits neointima formation through attenuation of migration and proliferation of vascular smooth muscle cells

Abstract

Graphical abstract

Highlights

Section snippets

Animals

Cell culture

SOD2 expression is increased in carotid artery after balloon withdrawal injury

Discussion

Acknowledgment

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Atherosclerosis

Free Radic. Biol. Med.

Atherosclerosis

J. Am. Coll. Cardiol.

J. Biol. Chem.

Free Radic. Biol. Med.

J. Mol. Cell. Cardiol.

Placenta

Drug eluting stents: friend or foe? A review of cellular mechanisms behind the effects of Paclitaxel and sirolimus eluting stents

Curr. Drug Metab.

The pathogenesis of atherosclerosis: a perspective for the 1990s

Nature

Xanthine oxidase-derived extracellular superoxide anions stimulate activator protein 1 activity and hypertrophy in human vascular smooth muscle via c-Jun N-terminal kinase and p38 mitogen-activated protein kinases

J. Hypertens.

Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms

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Original Contribution
Manganese superoxide dismutase inhibits neointima formation through attenuation of migration and proliferation of vascular smooth muscle cells