heme-arginate and Inflammation

Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.

Topics: 3T3 Cells; Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Adiposity; Animals; Arginine; Blood Glucose; Cell Line; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Heme; Heme Oxygenase (Decyclizing); Hyperglycemia; Inflammation; Insulin-Secreting Cells; Metalloporphyrins; Mice; Pilot Projects

Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation, has recently been considered to have protective roles against various pathophysiological conditions. Since we demonstrated that HO-1 overexpression inhibits atherosclerotic formation in animal models, we examined the effect of HO modulation on proinflammatory cytokine production, endothelial NO synthase (eNOS) expression, and endothelium-dependent vascular relaxation responses.. After HO-1 induction by heme arginate (HA), vascular endothelial cell cultures were exposed to oxidized low-density lipoprotein (oxLDL) or tumor necrosis factor-alpha (TNF-alpha). HA pretreatment significantly attenuated the production of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and macrophage colony-stimulating factor, suggesting that HO-1 induction attenuates proinflammatory responses. In addition, HO-1 overexpression also alleviated endothelial dysfunction as judged by restoration of attenuated eNOS expression after exposure to oxLDL and TNF-alpha. Importantly, impaired endothelium-dependent vascular relaxation responses in thoracic aortic rings from high-fat-fed LDL receptor knockout mice were also improved. These effects were observed by treatment with bilirubin not by carbon monoxide.. These results suggest that the antiatherogenic properties of HO-1 may be mediated predominantly through the action of bilirubin by inhibition of vascular endothelial activation and dysfunction in response to proinflammatory stresses.

Topics: Animals; Aorta; Aorta, Thoracic; Arginine; Bilirubin; Endothelial Cells; Endothelium, Vascular; Enzyme Induction; Gene Expression Profiling; Gene Expression Regulation; Heme; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; In Vitro Techniques; Inflammation; Lipoproteins, LDL; Membrane Proteins; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oligonucleotide Array Sequence Analysis; Tumor Necrosis Factor-alpha; Vasodilation