Abstract
Oxidative stress and inflammation are implicated in tissue remodeling, hypertrophy, and organ malfunction. Since heme-oxygenase (HO) is a cytoprotective enzyme with effects against oxidative stress and inflammation, we investigated the effects of upregulating HO with hemin on adipocyte hypertrophy, proteins of repair/regeneration including beta-catenin, Oct3/4 and Pax2 as well as pro-fibrotic/remodeling proteins like osteopontin and transforming growth factor-beta (TGF-β) in pericardial adipose tissue from obese Zucker rats (ZRs). Treatment with hemin significantly reduced pericardial adipose tissue inflammation/oxidative stress, suppressed osteopontin and TGF-β, and attenuated pericardial adipocyte hypertrophy in obese ZRs. These were associated with enhanced expression of the stem/progenitor-cell marker cKit; the potentiation of several proteins of regeneration including beta-catenin, Oct3/4, Pax2; and improved pericardial adipocyte morphology. Interestingly, the amelioration of adipocyte hypertrophy in hemin-treated animals was accompanied by improved adipocyte function, evidenced by increased levels of pericardial adipose tissue adiponectin. Furthermore, hemin significantly reduced hypertriglyceridemia and hypercholesteromia in obese ZRs. The protective effects of hemin were accompanied by robust potentiation HO activity and the total antioxidant capacity, whereas the co-administration of hemin with the HO inhibitor, stannous mesoporphyrin abolished the effects of hemin. These data suggest that hemin improves pericardial adipocyte morphology and function by enhancing proteins of repair and regeneration, while concomitantly abating inflammatory/oxidative insults and suppressing extracellular-matrix/profibrotic and remodeling proteins. The reduction of hypertriglyceridemia, hypercholesteromia, pericardial adiposity, and pericardial adipocyte hypertrophy with corresponding improvement of adipocyte morphology/function in hemin-treated animals suggests that HO inducers may be explored for the design of novel remedies against cardiac complications arising from excessive adiposity.