TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation.
BACKGROUND
Myocardial infarction (MI) results in remodeling of the myocardium and the extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) are critical regulators of ECM integrity via inhibiting matrix metalloproteinases (MMPs). TIMP2 is highly expressed in the heart and is the only TIMP that, in addition to inhibiting MMPs, is required for cell surface activation of pro-MMP2. Hence, it is difficult to predict the function of TIMP2 as protective (MMP-inhibiting) or harmful (MMP-activating) in heart disease.


OBJECTIVE
We examined the role of TIMP2 in the cardiac response to MI.


RESULTS
MI was induced in 11- to 12-week-old male TIMP2(-/-) and age-matched wild-type mice. Cardiac function was monitored by echocardiography at 1 and 4 weeks post-MI. ECM fibrillar structure was visualized using second harmonic generation and multiphoton imaging of unfixed/unstained hearts. Molecular analyses were performed at 3 days and 1 week post-MI on flash-frozen infarct, periinfarct, and noninfarct tissue. Membrane type 1 (MT1)-MMP levels and activity were measured in membrane protein fractions. TIMP2(-/-)-MI mice exhibited a 25% greater infarct expansion, markedly exacerbated left ventricular dilation (by 12%) and dysfunction (by 30%), and more severe inflammation compared to wild-type MI mice. Adverse ECM remodeling was detected by reduced density and enhanced disarray of fibrillar collagen in TIMP2(-/-)-MI compared to wild-type MI hearts. TIMP2 deficiency completely abrogated MMP2 activation but markedly increased collagenase activity, particularly MT1-MMP activity post-MI.


CONCLUSIONS
The MMP-inhibitory function of TIMP2 is a key determinant of post-MI myocardial remodeling primarily because of its inhibitory action on MT1-MMP. TIMP2 replenishment in diseased myocardium could provide a potential therapy in reducing or preventing disease progression.
Kandalam
Vijay
V
Department of Physiology, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Basu
Ratnadeep
R
Abraham
Thomas
T
Wang
Xiuhua
X
Soloway
Paul D
PD
Jaworski
Diane M
DM
Oudit
Gavin Y
GY
Kassiri
Zamaneh
Z
D000818:Animals; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D024022:Fibrillar Collagens / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036641:Microscopy, Fluorescence, Multiphoton; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D012720:Severity of Illness Index; D013318:Stroke Volume; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000172:deficiency* / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D024022:Fibrillar Collagens; C507096:Mmp14 protein, mouse; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D053511:Matrix Metalloproteinase 14