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 (ZDF). Echocardiographic, quantitative-RT-PCR, Western-blot, EIA and spectrophotometric analysis were used. In ZDF-rats, hemin administration increased HO-activity, normalised glycemia, potentiated insulin-signalling by enhancing insulin-receptor-substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K) and protein-kinase-B (PKB), suppressed pericardial-adiposity, cardiac-hypertrophy and left-ventricular longitudinal muscle-fiber-thickness, a pathophysiological feature of cardiomyocyte hypertrophy and correspondingly reduced systolic-blood-pressure and total-peripheral-resistance. In addition, hemin suppressed several pro-inflammatory/oxidative mediators including, NF-κB, c-Jun-N-terminal-kinase (cJNK), endothelin (ET-1), TNF-α, interleukin (IL)-6, IL-1β, activating-protein (AP-1) and 8-isoprostane, whereas the HO-blocker, stannous-mesoporphyrin (SnMP) nullified the hemin-effects. Furthermore, hemin reduced the pro-inflammatory macrophage-M1-phenotype, but enhanced macrophage-M2-phenotype that dampens inflammation. Interestingly, the hemin-effects were less-pronounced in healthy Zucker-lean-rats, suggesting greater selectivity of HO in unhealthy ZDF-rats. Since NF-κB activates TNF-α, IL6 and IL-1β, while TNF-α, JNK and AP-1 impair insulin-signalling, 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 expression of IRS-1, PI3K, PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. The hemin-induced preferential polarization of macrophages towards anti-inflammatory M2-phenotype in cardiac tissue and suppression of pericardial adiposity in ZDF-rats are novel findings. Collectively, our study unveils the beneficial effects of hemin on pericardial-adiposity, impaired insulin-signalling and diabetic-cardiomyopathy, and suggests that the multifaceted mechanisms include the suppression of inflammatory/oxidative mediators.
- Received October 2, 2012.
- Revision received February 24, 2013.
- Accepted February 25, 2013.
- The American Society for Pharmacology and Experimental Therapeutics