Myocardial recovery from ischemia-reperfusion is compromised in the absence of tissue inhibitor of metalloproteinase 4.
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.


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 membrane-type 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.
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Abhijit
A
Takawale
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Dong
D
Fan
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Ratnadeep
R
Basu
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Mengcheng
M
Shen
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Nirmal
N
Parajuli
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Wang
W
Wang
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Xiuhua
X
Wang
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.).
Gavin Y
GY
Oudit
From the Department of Physiology (A.T., D.F., R.B., M.S., W.W., X.W., G.Y.O., Z.K.) and Department of Medicine/Division of Cardiology (N.P., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada; and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (A.T., D.F., R.B., M.S., N.P., W.W., X.W., G.Y.O., Z.K.). z.kassiri@ualberta.ca.
Zamaneh
Z
Kassiri
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling; D000097792:Tissue Inhibitor of Metalloproteinase-4
D012313:RNA; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
reperfusion injury; tissue inhibitor of metalloproteinases