In
hypertension, elevated levels of oxidative/inflammatory mediators including
nuclear factor kappaB (
NF-kappaB), activating
protein (AP-1), c-Jun-NH2-terminal
kinase (JNK), and cell-regulatory
proteins such as
transforming growth factor beta (
TGF-beta), trigger the mobilization of extracellular matrix (ECM) leading to
fibrosis,
hypertrophy and impairment of cardiac function. Although the
heme oxygenase (HO) system is cytoprotective, its effects on cardiac
fibrosis and
hypertrophy in
deoxycorticosterone acetate (
DOCA-
salt)
hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer,
heme arginate against histopathological lesions in
DOCA-
hypertension. Treatment with
heme arginate restored physiological blood pressure, and abated
cardiac hypertrophy (3.75 +/- 0.12 vs. 3.19 +/- 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 +/- 0.62 vs. 4.39 +/- 0.63; n = 16, P < 0.01), left ventricular mass (2.48 +/- 0.14 vs. 2.01 +/- 0.09 g/kg body wt; n = 16, P < 0.01) and left-ventricular wall thickness (2.82 +/- 0.16 vs. 1.98 +/- 0.14 mm; n = 16, P < 0.01), whereas the HO inhibitor,
chromium mesoporphyrin, exacerbated
hypertrophy and cardiac lesions. The suppression of
cardiac hypertrophy was accompanied by a robust increase in HO-1, HO activity, cyclic
guanosine monophosphate (cGMP),
ferritin and the total
antioxidant capacity, whereas
8-isoprostane,
NF-kappaB, JNK,
AP-1,
TGF-beta,
fibronectin and
collagen-I were significantly abated. Correspondingly, histopathological parameters that depict progressive cardiac damage, including
fibrosis, interstitial/perivascular
collagen deposition,
scarring, muscle-fiber thickness, muscular
hypertrophy and coronary-arteriolar thickening were abated. Our study suggests that upregulating the HO system lowers blood pressure, potentiates the
antioxidant status in tissues, suppresses oxidative stress/mediators such as
NF-kappaB,
AP-1 and cJNK, and suppresses the mobilization of ECM
proteins like
TGF-beta,
collagen and
fibronectin, with corresponding reduction of cardiac histopathological lesion and
hypertrophy.