Myocardial Recovery from Ischemia-Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4
Background—Myocardial reperfusion following ischemia (I/R), while an effective approach in rescuing the ischemic myocardium, can itself trigger a number of adverse effects including aberrant remodeling of the myocardium and its extracellular matrix (ECM). Tissue inhibitor of metalloproteinases (TIMPs) protect the ECM against excess degradation by matrix metalloproteinases (MMPs). TIMP4 levels are reduced in myocardial infarction; however its causal role in progression of post-I/R injury has not been explored.
Methods and Results—In vivo I/R (20min ischemia, 1wk reperfusion) resulted in more severe systolic and diastolic dysfunction in TIMP4-/- mice with enhanced inflammation, oxidative stress (1d post-I/R), hypertrophy and interstitial fibrosis (1wk). Following an initial increase in TIMP4 (1d post-I/R), TIMP4 mRNA and protein decreased in the ischemic myocardium from WT mice by 1 wk post-I/R, and in tissue samples from patients with myocardial infarction, which correlated with enhanced activity of membrane-bound MMP, MT1-MMP. By 4wks post-I/R, WT mice showed no cardiac dysfunction, elevated TIMP4 levels (to baseline) and normalized MT1-MMP activity. TIMP4-deficient mice, however, showed exacerbated diastolic dysfunction, sustained elevation of MT1-MMP activity, and worsened myocardial hypertrophy and fibrosis. Acute I/R, ex vivo (20min or 30min ischemia, 45min reperfusion), resulted in comparable cardiac dysfunction in WT and TIMP4-/- mice.
Conclusions—TIMP4 is essential for recovery from myocardial I/R in vivo, primarily due to its MT1-MMP inhibitory function. TIMP4-deficiency does not increase susceptibility to acute I/R injury (ex vivo). Replenishment of myocardial TIMP4 could serve as an effective therapy in post-I/R recovery for patients with reduced TIMP4.
- Received January 14, 2014.
- Accepted May 13, 2014.