Cardiac function is adversely affected by pericardial adiposity. We investigated the effects of the
heme oxygenase (HO) inducer,
hemin on pericardial adiposity, macrophage polarization, and diabetic cardiopathy in Zucker diabetic fatty rats (ZDFs) with use of echocardiographic, quantitative real-time polymerase chain reaction, Western immunoblotting,
enzyme immunoassay, and spectrophotometric analysis. In ZDFs,
hemin administration increased HO activity; normalized glycemia; potentiated
insulin signaling by enhancing
insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and
protein kinase B (PKB)/Akt; suppressed pericardial adiposity,
cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte
hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor κB (NF-κB), cJNK,
c-Jun-N-terminal kinase (cJNK),
endothelin (ET-1),
tumor necrosis factor α (TNF-α),
interleukin (IL)-6, IL-1β, activating
protein 1 (AP-1), and
8-isoprostane, whereas the HO inhibitor,
stannous mesoporphyrin, nullified the effects. Furthermore,
hemin reduced the pro-inflammatory macrophage M1 phenotype, but enhanced the M2 phenotype that dampens
inflammation. Because NF-κB activates TNFα,
IL-6, and IL-1β and TNF-α, cJNK, and
AP-1 impair
insulin signaling, the high levels of these
cytokines in
obesity/diabetes would create a vicious cycle that, together with
8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. Therefore, the concomitant reduction of pro-inflammatory
cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced
glucose metabolism and amelioration of cardiac injury and function in
diabetic cardiomyopathy. The
hemin-induced preferential polarization of macrophages toward anti-inflammatory macrophage M2 phenotype in cardiac tissue with concomitant suppression of pericardial adiposity in ZDFs are novel findings. These data unveil the benefits of
hemin against pericardial adiposity, impaired
insulin signaling, and
diabetic cardiomyopathy and suggest that its multifaceted protective mechanisms include the suppression of inflammatory/oxidative mediators.