Matrix Metalloproteinase-2 Proteolysis of Calponin-1 Contributes to Vascular Hypocontractility in Endotoxemic Rats
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. Two hours before and 30 minutes after LPS, 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 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.
- Received November 22, 2011.
- Accepted December 5, 2011.
- © 2011 American Heart Association, Inc.