TIMP-3 Deficiency Leads to Dilated Cardiomyopathy

Abstract

Background-Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. Methods and Results-Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-␣ cytokine system, molecular hallmarks of human myocardial remodeling. Conclusions-TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.

Placental Growth Factor Regulates Cardiac Inflammation Through the Tissue Inhibitor of Metalloproteinases-3/Tumor Necrosis Factor-α–Converting Enzyme Axis

“…Our results seem to conflict with previous data showing that TIMP-3 KO, obtained by embryonic knockdown of the gene, led to natural deterioration of cardiac structure and function with aging 30 and accelerated transition to heart failure on TAC. 16 These effects were ascribed mainly to a dysregulated TACE activation and excessive cytokine production, leading to exacerbated inflammation, fibrosis, and hypertrophy and recognizing that maladaptive matrix remodeling promotes abnormal cardiac structure and function.…”

Curcumin prevents and reverses murine cardiac hypertrophy

“…Inflammation plays an important role in the progression to cardiac hypertrophy (20), and perivascular infiltration by neutrophils and macrophages has been observed in the hearts of several animal species subjected to AB (30,31). After curcumin administration, we observed marked attenuation of leukocyte infiltration and cytokine production, suggesting potential cross-talk between leukocyte infiltration and inflammation in modulating the microenvironment for the development of cardiac hypertrophy.…”

Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats

“…Additionally, the present study demonstrates that fetal hypoxia increases TIMP-3 and TIMP-4 expression levels in both fetal and neonatal hearts, suggesting another possible mechanism in the hypoxia-mediated downregulation of myocyte proliferation. In addition to the roles in modulating MMPs, it has been demonstrated that both TIMP-3 and TIMP-4 play a key role in inhibiting cardiomyocyte proliferation in rat hearts possibly in a MMP-independent and receptor-mediated manner (13,16,17,42).…”