Disruption of the equilibrium of collagen Sample Clauses

Disruption of the equilibrium of collagen synthesis The collagen synthesis and degradation in the heart is kept in equilibrium. This process is maintained by a variety of hormones and cytokines of which matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are important (Xxxxxx et al., 2008). The effector hormones of the renin-angiotensin system, inflammatory cytokines (eg TGF-β1), growth factors (eg insulin-like growth factor) and degradation fragments from increased MMP activity, have been shown to have potent profibrotic effects. By contrast, bradykinin, nitric oxide, natriuretic peptide, and glucocorticoids have been shown to promote collagenolysis. An excess of stimulators, due either to absolute stimulator overproduction or to their relative overabundance because of a deficit in inhibitor formation, can promote fibrosis. In the setting of hypertensive heart disease (HHD), this equilibrium is disrupted, with activation of the RAS system and overproduction of AngII leading to fibrosis. As fibrosis progresses the existing collagenous matrix increases in dimension resulting in interstitial cardiac fibrosis. There is accumulation of thick collagen fibres around small intramyocardial coronary arteries resulting in perivascular fibrosis (Xxxxx et al., 1988). These fibres then radiate into the intermuscular spaces and may merge with co-existing interstitial cardiac fibrosis. Later, areas of cell necrosis are observed and lead to microscopic scar formation (Xxxxx et al., 1989). A key mediator of the pro-fibrotic effect of AngII is oxidative stress. Oxidative stress is also implicated in the downstream signalling pathways of the RAAS in many pathological settings.