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Articles by V Kandalam
Total Records ( 3 ) for V Kandalam
  V Kandalam , R Basu , T Abraham , X Wang , P. D Soloway , D. M Jaworski , G. Y Oudit and Z. Kassiri
 

Rationale: 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.

Methods and 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.

  D Guo , Z Kassiri , R Basu , F. L Chow , V Kandalam , F Damilano , W Liang , S Izumo , E Hirsch , J. M Penninger , P. H Backx and G. Y. Oudit
  Rationale:

Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K), the isoform linked to G protein–coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial.

Objective:

To characterize molecular and cellular responses of the PI3K knockout (KO) mice to biomechanical stress.

Methods and Results:

In response to pressure overload, PI3KKO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3. In contrast, isolated single cardiomyocytes from banded PI3KKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KKO mice. β-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3KKO mice resulted in reduced cell adhesion. The β-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3KKO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels.

Conclusions:

The enhanced propensity to develop heart failure in the PI3KKO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/β-catenin cell adhesion complex. β-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs.

  A. E Awad , V Kandalam , S Chakrabarti , X Wang , J. M Penninger , S. T Davidge , G. Y Oudit and Z. Kassiri
 

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts. rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K) as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3K. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and TNF–/– mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3K, thereby contributing to adverse myocardial remodeling in disease.

 
 
 
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