Letter by Pinto and Heymans Regarding Article, “Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice”
To the Editor:
We have read with great interest the recent article by Cheung et al,1 revealing that matrix metalloproteinase-9 (MMP-9)–deficient mice had increased coxsackievirus B3 (CVB3) replication and resulting inflammation and injury in CVB3-induced myocarditis.1 These findings were to some extent unexpected considering our previous findings that systemic overexpression of the tissue inhibitor of MMPs (TIMP-1) reduced cardiac inflammation and prevented adverse remodeling and dysfunction in CVB3 myocarditis.2 To make it even more complicated, inhibition of TIMP-1 significantly decreased inflammation and injury in CVB3-induced myocarditis, despite lack of differences in viral load or T-cell function.3 What to learn from these seemingly paradoxical studies?
The first question is whether the results are truly discrepant? We demonstrated that a broad inhibition of MMPs, decreased CVB3-induced cardiac inflammation and function loss. The now-published report1 shows that a complete loss of MMP-9 increased replication of CVB3 and thereby resulted in a higher degree of cardiac inflammation and function loss. Thus, the beneficial effect MMP inhibition that we reported is most probably not due to inhibition of MMP-9 activity.
A paradoxical role for selective versus nonspecific MMP inhibition was also observed in cardiac allograft rejection, another T-cell–dependent disease. Use of a broad spectrum MMP inhibitor significantly reduced T-cell infiltration and improved survival of the cardiac allograft, whereas MMP-9 gene-inactivated mice had significantly increased cellular infiltration and impaired cardiac allograft survival.4 Whether TIMP-1 deficiency or overexpression also alters cardiac allograft function and survival warrants further investigation.
What about the role of MMP-9 in other cardiac diseases? Independent studies clearly showed that deficiency of MMP-9 but also of MMP-2 significantly reduced inflammation and improved cardiac function after myocardial infarction or hypertension (reviewed in Vanhoutte et al5). Nonspecific MMP inhibition with synthetic MMP inhibitors or TIMP-1 overexpression reduced adverse cardiac remodeling and failure after myocardial infarction, whereas TIMP-1 deficiency exacerbated left ventricular dilatation after myocardial infarction. A disparate role for MMP-9 in cardiac inflammation in myocardial infarction compared with myocarditis may relate to the different inflammatory cells and cytokines involved and their disparate regulation by MMP-9.
What about TIMP-1 itself? A complete loss of TIMP-1 decreased CVB3-induced cardiac inflammation and function loss, whereas we reported that a short strong systemic increase in TIMP-1 actually decreased CVB3-induced cardiac dilatation and function loss. These findings could be explained by the fact that TIMP-1 plays a function in retaining the inflammatory cells to areas of CVB3 infection, inducing myocarditis, injury, and dysfunction without affecting MMP levels.3 In contrast, supraphysiological levels of TIMP-1 may prevent the deleterious effect of CVB3-induced MMPs, reducing adverse cardiac dilation.
In conclusion, therapeutic inhibition of MMPs should be restricted for well-specified cardiac diseases with a comprehensive diagnosis of the underlying cause. Thus, specific MMP-2 or -9 inhibitors may be beneficial for the treatment of acute ischemic or hypertensive heart disease, but should be used with care in acute viral myocarditis.
Sources of Funding
This work was supported by research grants of the Netherlands Heart Foundation (NHS, 2005B082 and 2007B036), a VIDI grant of The Dutch Foundation for Scientific Research, and an Ingenious Hypercare NoE EU grant to Dr Heymans. Dr Pinto is an established investigator of the Netherlands Heart Foundation.
Cheung C, Marchant D, Walker EK, Luo Z, Zhang J, Yanagawa B, Rahmani M, Cox J, Overall C, Senior RM, Luo H, McManus BM. Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice. Circulation. 2008; 117: 1574–1582.
Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH, Padalko E, Neyts J, Schultheiss HP, Van de Werf F, Carmeliet P, Pinto YM. Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation. 2006; 114: 565–573.
Vanhoutte D, Schellings M, Pinto Y, Heymans S. Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window. Cardiovasc Res. 2006; 69: 604–613.