Role of A Disintegrin and Metalloproteinases (ADAMs)- 15 and 17 in Cardiac Remodelling Following Pressure Overload
Creators: Aujla, Preetinder K
Publisher: name: University of Alberta Library
Year: 2024

<p>Myocardial remodeling is a critical process in response to cardiac stress or injury, which includes changes in the cardiomyocyte size, the extracellular matrix (ECM), and cell-ECM interactions. Cardiac hypertrophy is the morphological increase in the myocardial mass by an increase in the cardiomyocyte size. This hypertrophy initially is compensatory such that the heart maintains normal contractile function, however, in the face of increased or prolonged stress, hypertrophy can progress to decompensatory remodeling marked by dilation of the ventricles, a hallmark of heart disease in which diastolic and/or systolic functions of the heart are compromised. Pathological pathways are mediated by angiotensin II, catecholamines, or mechanical stress, all leading to the initiation of different downstream signaling. <br>
A disintegrin and metalloproteinases (ADAMs) are Zn2+ dependent, membrane-bound enzymes that are capable of both proteolytic and adhesive functions leading to diverse tissue remodeling. ADAMs consist of a prodomain, metalloproteinase domain, disintegrin domain, cysteine-rich domain, epidermal growth factor (EGF) – like domain, transmembrane domain, and cytoplasmic domain. The metalloproteinase domain is responsible for the shedding of membrane-bound molecules, such as growth factors and cytokines, while the disintegrin domain can bind to integrins to mediate cell-cell interactions. Unique in the ADAMs family is ADAM15, which in addition to its shared function with other ADAMs, is also able to degrade ECM proteins. Information on the role of ADAM15 in cardiac diseases is severely lacking. ADAM15 is expressed in cardiac cells and its expression has been found to be increased in the left ventricle following myocardial infarction and in patients with dilated cardiomyopathy. ADAM17, also known as tumor necrosis factor  (TNF) converting enzyme (TACE), is the most extensively studied ADAM, with over 80 substrates identified. ADAM17-deficient mice die shortly after birth and present with defects in the aortic, pulmonic, and tricuspid valves. ADAM17 activity is increased in murine models of DCM. <br>
The research in this thesis reveals the novel role of ADAM15 and ADAM17 in mediating cardiac remodelling following pressure overload. ADAM15 was found to have a sex-specific cardioprotective role in limiting the disease progression in cardiomyopathies associated with increased mechanical stress. ADAM15 is downregulated in patients with eccentric hypertrophy and heart failure, but not in those patients with concentric hypertrophic hearts. We found that loss of ADAM15 in male mice lead to increased hypertrophy and dilation following cardiac pressure overload. These were attributed to an increase in MAPK signalling and the calcineurin-NFAT pathway. Blocking calcineurin with its inhibitor, cyclosporin A, blocked the increased eccentric hypertrophy seen in the cardiac pressure overloaded Adam15-/- hearts and were comparable to their wild-type controls. In the female mice, however, there was no difference in hypertrophy following cardiac pressure overload. Both Adam15-deficient male and female mice aged 1 year had no baseline phenotype and were comparable to their wild-type controls. <br>
Interestingly, we found that full body Adam15-deficiency resulted in increased cardiac hypertrophy but not a concurrent increase in fibrosis, suggesting an independent and uncoupled role for ADAM15 in mediating these processes. Our lab has previously reported that cardiomyocyte-specific deletion of ADAM17 resulted in increased hypertrophy following pressure overload. Since we established that ADAM’s may have independent roles in mediating cardiac hypertrophy versus fibrosis, we next examined how Adam17-deficiency in myofibroblasts may impact cardiac fibrosis following pressure overload induced by transverse aortic constriction (TAC) or Angiotensin II (AngII) infusion. Loss of ADAM17 in myofibroblasts resulted in increased interstitial and perivascular fibrosis following AngII infusion. In contrast, when pressure overload was induced by mechanical stretch (TAC), loss of ADAM17 in myofibroblasts resulted in increased perivascular fibrosis and decreased interstitial fibrosis. These TAC hearts also had increased expression of immune cells, indicating a greater inflammatory response. Both pressure overloaded models showed no difference in cardiac hypertrophy, suggesting that hypertrophy and fibrosis were uncoupled.</p>