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.