Molecular Mechanism of Heme Oxygenase-1 (Ho-1) in Inhibiting Angiotensin Ii-Induced Collagen Expression in Atrial Fibroblasts

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. Structural remodeling such as extracellular matrix accumulation including collagen deposition in the atria is often irreversible in AF-related atrial remodeling, which makes AF a refractory disease to treat. Attenuation and reversal of structural remodeling and atrial fibrosis have increasingly become the focus of attempts at therapeutic innovation, and several agents have shown efficacy in animal models and humans like angiontensin II receptor blockers, spironolactone, pirfenidone, statins and omega-3 poly-unsaturated fatty acids. Oxidative stress is a potential therapeutic target. Heme oxygenase-1 (HO-1) degrades heme to form carbon monoxide (CO), free iron and biliverdin, the latter being subsequently converted into bilirubin. These products may acts in protection from oxidative stress, a process that has been suggested to be important in the pathophysiology of several cardiovascular disease. Potential mechanisms by which HO-1 provides protection against cardiopathology include antioxidant activity of bilirubin or CO. We hypothesize HO-1 induction may provide a therapeutic innovation for atrial fibrosis and AF. We will evaluate the effect of HO-1 overexpression, addition of CO or biliverdin/biliburin in inhibiting angiotensin II-induced collagen expression in cultured rat atrial fibroblasts and in rat for animal study. Our preliminary data showed overexpression of HO-1 and CO released from CORM-2 can reduce angiontensin II-induced collagen expression in atrial fibroblasts. Further studies in detail will be performed to explain the mechanism and its functional significance in AF inducibility in a rat Langehdorff model.

Project ID:PC10108-0738
External Project ID:NSC101-2314-B182A-135