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Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis.

ABSTRACT: Increased interferon (IFN)-? signaling in patients with insufficient coronary collateralization and an inhibitory effect of IFN? on collateral artery growth in mice have been reported. The mechanisms of IFN?-induced inhibition of arteriogenesis are unknown. In stimulated monocytes from patients with chronic total coronary artery occlusion and decreased arteriogenic response, whole genome expression analysis showed increased expression of IFN?-regulated genes. Immunohistochemically, the IFN? receptor was localized in the vascular media of murine collateral arteries. Treatment of vascular smooth muscle cells (VSMC) with IFN? resulted in an attenuated proliferation, cell-cycle arrest, and increased expression of cyclin-dependent kinase inhibitor-1A (p21). The growth inhibitory effect of IFN? was attenuated by inhibition of p21 by RNA interference. IFN?-treated THP1 monocytes showed enhanced apoptosis. Subsequently, we tested if collateral artery growth can be stimulated by inhibition of IFN?-signaling. RNA interference of the IFN? receptor-1 (IFNAR1) increased VSMC proliferation, cell cycle progression, and reduced p21 gene expression. IFN? signaling and FAS and TRAIL expression were attenuated in monocytes from IFNAR1(-/-) mice, indicating reduced monocyte apoptosis. Hindlimb perfusion restoration 1 week after femoral artery ligation was improved in IFNAR1(-/-) mice compared with wild-type mice as assessed by infusion of fluorescent microspheres. These results demonstrate that IFN? inhibits collateral artery growth and VSMC proliferation through p21-dependent cell cycle arrest and induction of monocyte apoptosis. Inhibition of IFN? stimulates VSMC proliferation and collateral artery growth.

SUBMITTER: Schirmer SH

PROVIDER: S-EPMC2966083 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis.

Schirmer Stephan H SH Bot Pieter T PT Fledderus Joost O JO van der Laan A M AM Volger Oscar L OL Laufs Ulrich U Böhm Michael M de Vries Carlie J M CJ Horrevoets Anton J G AJ Piek Jan J JJ Hoefer Imo E IE van Royen Niels N

The Journal of biological chemistry 20100824 45

Increased interferon (IFN)-β signaling in patients with insufficient coronary collateralization and an inhibitory effect of IFNβ on collateral artery growth in mice have been reported. The mechanisms of IFNβ-induced inhibition of arteriogenesis are unknown. In stimulated monocytes from patients with chronic total coronary artery occlusion and decreased arteriogenic response, whole genome expression analysis showed increased expression of IFNβ-regulated genes. Immunohistochemically, the IFNβ rece ...[more]

PMID: 20736166

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Project description:Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (? 2 ?m by 0.5 ?m), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.

Dataset Information

Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis.

Publications

Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis.

Similar Datasets

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