Myocardial Recovery From Ischemia–Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4

Abstract

Background-Myocardial reperfusion after ischemia (I/R), although an effective approach in rescuing the ischemic myocardium, can itself trigger several adverse effects including aberrant remodeling of the myocardium and its extracellular matrix. Tissue inhibitor of metalloproteinases (TIMPs) protect the extracellular matrix 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 (20-minute ischemia, 1-week reperfusion) resulted in more severe systolic and diastolic dysfunction in TIMP4 −/− mice with enhanced inflammation, oxidative stress (1 day post-I/R), hypertrophy, and interstitial fibrosis (1 week). After an initial increase in TIMP4 (1 day post-I/R), TIMP4 mRNA and protein decreased in the ischemic myocardium from wild-type mice by 1 week post-I/R and in tissue samples from patients with myocardial infarction, which correlated with enhanced activity of membrane-bound MMP, membrane-type 1 MMP. By 4 weeks post-I/R, wild-type mice showed no cardiac dysfunction, elevated TIMP4 levels (to baseline), and normalized membranetype 1 MMP activity. TIMP4-deficient mice, however, showed exacerbated diastolic dysfunction, sustained elevation of membrane-type 1 MMP activity, and worsened myocardial hypertrophy and fibrosis. Ex vivo I/R (20-or 30-minute ischemia, 45-minute reperfusion) resulted in comparable cardiac dysfunction in wild-type and TIMP4 −/− mice. Conclusions-TIMP4 is essential for recovery from myocardial I/R in vivo, primarily because of its membrane-type 1 MMP inhibitory function. TIMP4 deficiency does not increase susceptibility to ex vivo I/R injury. Replenishment of myocardial TIMP4 could serve as an effective therapy in post-I/R recovery for patients with reduced TIMP4. (Circ Heart Fail. 2014;7:652-662.)

Inflammation in the pleural cavity following injection of multi-walled carbon nanotubes is dependent on their characteristics and the presence of IL-1 genes

“…However, there is also evidence that it may do the opposite, namely decrease fibrosis (Takawale et al, 2014). In the present study, Timp4 was downregulated by both doses of CNT-1 and the highest dose of CNT-2 and asbestos.…”

The role of TIMPs in regulation of extracellular matrix proteolysis

“…Following myocardial ischemia/reperfusion, ECM remodeling often occurs with an initial fibrotic response followed by ECM turnover. In mice lacking TIMP4, interstitial fibrosis was enhanced one week following injury compared to wild type mice [67]. Interestingly, this augmented fibrosis was associated with greater MMP14 activity as well as increased inflammation, suggesting that TIMP4 regulates ECM deposition through inhibition of MMP14 and restriction of inflammation [67].…”

Gene Expression Profiling of H9c2 Cells Subjected to H₂O₂-Induced Apoptosis with/without AF-HF001

“…Structural remodeling of the extracellular matrix is an important contributor to abnormal ventricular TIMP4 inhibits MMP-mediated degradation of excess extracellular matrix and reduces myocardial infarction in vivo in I/R mice. 17) Chaturvedi et al 18) reported that TIMP4 attenuates oxidative stress and induces the differentiation of cardiac progenitor cells into cardiomyocytes. Our data demonstrated that TIMP4 expression upon H 2 O 2 treatment (−1.85-fold) was up-regulated in cells that were also treated with AF-HF001 (1.97-fold).…”