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  • Title: Matrix metalloproteinase-2 proteolysis of calponin-1 contributes to vascular hypocontractility in endotoxemic rats.
    Author: Castro MM, Cena J, Cho WJ, Walsh MP, Schulz R.
    Journal: Arterioscler Thromb Vasc Biol; 2012 Mar; 32(3):662-8. PubMed ID: 22199370.
    Abstract:
    OBJECTIVE: Matrix metalloproteinase (MMP)-2 is activated in aorta during endotoxemia and plays a role in the hypocontractility to vasoconstrictors. Calponin-1 is a regulator of vascular smooth muscle tone with similarities to troponin, a cardiac myocyte protein that is cleaved by MMP-2 in myocardial oxidative stress injuries. We hypothesized that calponin-1 may be proteolyzed by MMP-2 in endotoxemia-induced vascular hypocontractility. METHODS AND RESULTS: Rats were given a nonlethal dose of bacterial lipopolysaccharide (LPS) or vehicle. Some rats were given the MMP inhibitors ONO-4817 or doxycycline. Six hours later, plasma nitrate+nitrite increased >15-fold in LPS-treated rats, an effect unchanged by doxycycline. Both ONO-4817 and doxycycline prevented LPS-induced aortic hypocontractility to phenylephrine. LPS activated MMP-2 in the aorta by S-glutathiolation. Calponin-1 levels decreased by 25% in endotoxemic aortae, which was prevented by doxycycline. Calponin-1 and MMP-2 coimmunoprecipitated and both exhibited uniform cytosolic staining in medial vascular smooth muscle cells. In vitro incubation of calponin-1 with MMP-2 led to calponin-1 degradation and appearance of its cleavage product. CONCLUSION: Calponin-1 is a target of MMP-2, which contributes to endotoxemia-induced vascular hypocontractility.
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