Matrix metalloproteinases (MMPs) have been shown to play significant roles in a number of physiological as well as pathological processes. Best known to proteolyse components of the extracellular matrix, MMPs have recently been discovered to also target a growing list of proteins apart from these, both inside and outside the cell. MMPs have also been traditionally thought of as enzymes involved in chronic processes such as angiogenesis, remodelling and atherosclerosis on a days-week time-scale. However they are now understood to also act acutely in response to oxidative stress on a minutes time-scale on non-extracellular matrix substrates. This review focuses on the acute actions and both extracellular and intracellular targets of two prominent MMP family members, MMP-2 and -9, in cardiovascular diseases including ischaemia/reperfusion injury, inflammatory heart disease, septic shock and pre-eclampsia. Also discussed are various ways of regulating MMP activity, including post-translational mechanisms, the endogenous tissue inhibitors of metalloproteinases and pharmacological inhibitors. A comprehensive understanding of MMP biology is necessary for the development of novel pharmacological therapies to combat the impact of cardiovascular disease.

The strong inflammatory reaction that occurs in the heart during the acute phase of Trypanosoma cruzi infection is modulated by cytokines and chemokines produced by leukocytes and cardiomyocytes. Matrix metalloproteinases (MMPs) have recently emerged as modulators of cardiovascular inflammation. In the present study we investigated the role of MMP-2 and MMP-9 in T. cruzi-induced myocarditis, by use of immunohistochemical analysis, gelatin zymography, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction to analyze the cardiac tissues of T. cruzi-infected C57BL/6 mice. Increased transcripts levels, immunoreactivity, and enzymatic activity for MMP-2 and MMP-9 were observed by day 14 after infection. Mice treated with an MMP inhibitor showed significantly decreased heart inflammation, delayed peak in parasitemia, and improved survival rates, compared with the control group. Reduced levels of cardiac tumor necrosis factor-alpha, interferon-gamma, serum nitrite, and serum nitrate were also observed in the treated group. These results suggest an important role for MMPs in the induction of T. cruzi-induced acute myocarditis.

No abstract

Background and purpose: The acute vascular inflammatory dysfunction associated with endotoxaemia may reflect an imbalance between matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), induced by the endotoxin. This possibility was tested in rat aortic tissue. Experimental approaches: Tone induced by phenylephrine in aortic rings was measured after exposure in vitro to ambient lipopolysaccharide (LPS) or the proinflammatory cytokine interleukin-1b (IL-1b) for 6h, with or without MMP inhibitors (doxycycline or GM6001). Gelatinase and MMP activities, TIMP proteins and contractility were measured in aortae taken from rats 6h after receiving LPS in vivo. Key results: Inhibition of MMP prevented the loss of phenylephrine-induced tone in aortic rings after LPS or IL-1b. IL-1b also increased release of MMP-2 activity from aortic tissue. In aortae exposed in vivo to LPS, net gelatinase, MMP-9 activities and TIMP-1 protein levels were increased, whereas TIMP-4 was reduced. These aortae were hypocontractile to both phenylephrine and KCl. Hypocontractility was partially reversed by doxycycline ex vivo. Conclusions and Implications: MMP inhibitors ameliorate vascular hyporeactivity induced by either LPS or IL-1b in vitro. LPS in vivo alters the balance between MMPs and TIMPs, contributing to vascular dysfunction which is partially reversed by MMP inhibitors. Vascular MMPs are activated as a result of LPS or IL-1b-induced stress and contribute to the hyporeactivity of blood vessels to vasoconstrictors.

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 nitrateϩnitrite increased Ͼ15-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. Key Words: metalloproteinases Ⅲ calponin-1 Ⅲ endotoxemia Ⅲ lipopolysaccharide Ⅲ vascular hypocontractility S epsis remains one of the most common causes of death worldwide. 1 Its cardiovascular manifestations include myocardial dysfunction and severe arterial hypotension caused in part by vascular hyporeactivity to vasoconstrictors. 2 Several mechanisms 3 including lipopolysaccharide (LPS)-and interleukin-1␤-mediated activation of inducible nitric oxide (NO) synthase, excess biosynthesis of NO, 4,5 and peroxynitrite (ONOO Ϫ ) 6,7 in the vascular wall are important mediators of the vascular dysfunction in sepsis. ONOO Ϫ directly activates matrix metalloproteinases (MMPs), 8,9 a group of zinc-dependent endopeptidases best known for their ability to degrade extracellular matrix proteins, causing vascular dysfunction and remodeling in many cardiovascular diseases. 10 -16 MMPs are synthesized as inactive zymogens in several cells, including vascular smooth muscle that express 72 kDa MMP-2 abundantly. 10 It is activated by proteolytic removal of the autoinhibitory propeptide domain 10 or, alternatively, by S-glutathiolation of a critical cysteine in this propeptide, on reaction with ONOO Ϫ and glutathione, resulting in 72 kDa S-glutathiolated MMP-2. 9 However, whether MMP-2 activation occurs by S-glutathiolation in the vasculature is unknown.Studies have implicated MMPs and the beneficial effects of MMP inhibition in experimental models of sepsis. 17-23 MMP-2 plays an important role in LPS-induced vascular hypocontractility in rats. In vivo treatment with the MMP inhibitor doxycycline attenuated LPS-induced increase in vascular MMP-2 activity and protected against the loss of vascular contractile tone. 18 Doxycyclin...