TIMP-3 inhibits neonatal cardiomyocyte proliferation and protects against cardiac rupture following myocardial infarction

Cardiac development and function are dependent on the proper functioning of the extracellular matrix (ECM). Myocardial ECM remodelling is mediated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). TIMP-3 is ECM bound, and its expression is reduced in the failing heart. However little is known regarding the role of TIMP-3 in postnatal heart development and scar healing post myocardial infarction (MI). This thesis investigated the role of TIMP-3 in cardiomyocyte proliferation, a process central to neonatal heart development, as well as the protective effects of TIMP-3 following MI in adult mice.;Scar healing is an important process following MI and ECM remodelling plays a key role in that process. However, the role of TIMP-3 in scar healing post-MI is not fully understood. I hypothesized that TIMP-3 deficiency impairs scar healing leading to increased cardiac rupture post-MI. To test this hypothesis, TIMP-3-/- and wild-type mice were subjected to MI induced by coronary artery ligation. My results showed that loss of TIMP-3 led to increased mortality post-MI due to increased incidence of cardiac rupture. Furthermore, the increased cardiac rupture not only resulted from an increase in collagen degradation due to the elevated MMP activity but also a decrease in collagen expression due to increased EGF levels.;In conclusion, TIMP-3 inhibits cardiomyocyte proliferation in the neonate and protects against cardiac rupture following MI in the adult. These effects are mediated by inhibition of EGF signalling in cardiomyocytes and cardiac fibroblasts, respectively.;Keywords: TIMP-3, eNOS, cardiomyocytes, proliferation, EGF, collagen, signal transduction, myocardial infarction.;Fetal and neonatal cardiomyocytes undergo significant proliferation. Our lab has previously shown that nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) promotes neonatal cardiomyocyte proliferation. Using primary cultures of neonatal cardiomyocytes, I demonstrated that eNOS derived NO promotes neonatal cardiomyocyte proliferation through inhibition of TIMP-3. The effect of NO on TIMP-3 expression is mediated by S-nitrosylation of AP-1. I also investigated the mechanism through which TIMP-3 exerts its anti-proliferative effects. My results showed that TIMP-3 inhibits epidermal growth factor (EGF) signalling which leads to increased p27 expression and thus inhibition of cardiomyocyte proliferation.