Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

Abstract

Deoxycorticosterone acetate-induced hypertension is a volume overload and human primary aldosteronism model characterized by severe cardiac lesions attributed to elevated inflammation, oxidative stress, fibrosis, and hypertrophy. An important cytoprotective pathway that counteracts tissue insults is the heme oxygenase (HO) system. Although the HO-1 gene promoter contains consensus binding sites for proinflammatory/oxidative transcription factors like nuclear factor-kappaB, activating protein (AP)-1, and AP-2, the effects of HO inducers on these transcription factors in cardiac lesions of deoxycorticosterone acetate hypertension are not fully understood. Hemin therapy normalized systolic blood pressure and markedly reduced the left:right ventricular ratio, left ventricular wall thickness, and left ventricle:body weight ratio, whereas the HO blocker, chromium mesoporphyrin, exacerbated cardiac fibrosis/hypertrophy in deoxycorticosterone acetate-hypertensive rats. The cardioprotection by hemin was accompanied by increased HO-1, HO activity, cGMP, superoxide dismutase, catalase, the total antioxidant capacity alongside the reduction of 8-isoprostane, AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase, whereas chromium mesoporphyrin abolished the hemin effects. Furthermore, hemin therapy attenuated transforming growth factor-beta(1) and extracellular matrix proteins like fibronectin and collagen, with a corresponding reduction of histopathologic lesions, including longitudinal/cross-sectional muscle fiber thickness, scarring, muscular hypertrophy, coronary arteriolar thickening, and collagen deposition. The suppression of AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase proinflammatory/oxidative mediators in the left ventricle of hemin-treated animals is a novel observation that may account for cardioprotection in deoxycorticosterone acetate hypertension. By concomitantly upregulating HO activity and cGMP and potentiating the total antioxidant status, hemin therapy reduced hypertension, suppressed oxidative stress, and attenuated extracellular matrix and remodeling proteins, with a reduction of histopathologic lesions that characterize cardiac fibrosis, hypertrophy, and end-stage organ damage.