Abstract 160: Tuberosis Sclerosis Complex 1 Mediated Neointima Formation and Arterial Thrombosis Following Vascular Injury

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Objectives: Vascular injury and thrombosis are main leading causes of cardiovascular diseases. Tuberous sclerosis complex (TSC) is a genetic disorder caused by heterozygous mutations in either of two genes, TSC1 and TSC2. Although role of TSCs has been implicated in cardiovascular diseases, the tissue- and isoform-specific roles of TSCs in the vascular response to injury are not known.

Methods and Results: To determine the role of TSC1 in arterial injury and thrombosis, we generated vascular smooth muscle cell-specific TSC1 conditional knockout mice (TSC1SM22-/-) by crossing vascular smooth muscle cell-specific Cre (SM22Cre) mice with TSC1flox/flox mice and performed carotid artery ligation in haploinsufficient TSC1 conditional knockout mice (TSC1SM22+/-) compared with that of WT or haploinsufficient TSC2 knockout mice (TSC2+/-). Acute carotid artery occlusion was investigated by 5% ferric chloride injury. Arterial thrombosis and neointima formation were measured at 14 days after arterial ligation. Expression of proteins was observed by immunoblot analysis. The neointima formation was significantly increased in TSC1SM22+/- mice (intimal thickness/medial thickness ratio; 1.14 ± 0.14, p<0.001) compared with that of WT mice (0.13 ± 0.03). Two weeks after arterial injury, arterial thrombus area was increased in TSC1SM22+/- mice (thrombus area/luminal area ratio; 72.1 ± 4.4, p<0.001) compared with that of WT mice (0.1 ± 0.0) but there are no significant effect in acute arterial thrombosis induced by ferric chloride. Loss of TSC1 and hyper-activation of mammalian target of rapamycin complex 1 including mTOR and S6 proteins were observed by immunoblot analysis of carotid artery tissue lysates of TSC1SM22+/- mice compared with that of WT.

Conclusion: These findings suggest that regulation of TSC1 and mTOR might be useful for therapeutic intervention in vascular injury and thrombosis.

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