HMG-CoA Reductase Inhibitor, Simvastatin Is Effective in Decreasing Degree of Myocarditis by Inhibiting Metalloproteinases Activation

Abstract

Background: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases’ (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). Methods: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. Results: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. Conclusions: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.

RhoA/ROCK Pathway Is Upregulated in Experimental Autoimmune Myocarditis and Is Inhibited by Simvastatin at the Stage of Myosin Light Chain Phosphorylation

“…Inflammatory cell infiltrations present in the EAM group in the perimysium and between cardiomyocytes, also in the form of thick clusters, were less intense in the groups receiving simvastatin, especially in the group treated with a higher dose. The number of multinucleated giant cells was also the lowest in this group [17].…”

“…Other EAM (EAM, n = 5)-induced rats and unimmunized rats (C, n = 8) received the vehicle orally by gastric gavage for 3 weeks from day 0 to day 21. Since the current study is part of a project and the results of its first part have already been published [17], due to the insufficient amount of tissue remaining after the analyses in the previous part, group C in the Western blot analysis consisted of 4 or 5 samples.…”

“…To our knowledge, there are no other scientific studies on the RhoA/ROCK pathway in EAM pathology and the effect of RhoA/ROCK pathway kinase inhibitors on its intensity. We have previously shown that the simvastatin treatment reduces mechanical cardiac dysfunction, myofilament damage, and troponin I degradation in EAM by inhibiting metalloproteinase 9 (MMP-9) activity [17]. We also showed that simvastatin has a protective effect on cardiac systolic function in an acute ischemia-reperfusion model by inhibiting the RhoA pathway and is independent of reductions in metalloprotease 2 (MMP-2) activity [18].…”

The Protective Effect of Simvastatin on the Systolic Function of the Heart in the Model of Acute Ischemia and Reperfusion Is Due to Inhibition of the RhoA Pathway and Independent of Reduction of MMP-2 Activity

“…The theory that statins may induce epigenetic control of MMP was also tested [ 12 ]. We previously demonstrated a reduction in mechanical cardiac dysfunction, damage to myofilaments, and a reduction in troponin I degradation by simvastatin in a model of myocarditis, which exerted this effect by inhibiting MMP-9 activity [ 13 ].…”

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“…Circulating MMP-9 has been reported as a promising biomarker to predict atherosclerotic plaques, plaque instability as well as CVD [5][6][7] . Statins have pleiotropic effects in vivo, such as influencing signalling systems that inhibit MMPs 8 . The peripheral levels of MMP-2 and MMP-9 can be used as indicators of heart failure and for identifying individuals who would benefit from a specific therapeutic intervention involving the MMP pathway 9 .…”