The Heme Oxygenase System Selectively Suppresses the Proinflammatory Macrophage M1 Phenotype and Potentiates Insulin Signaling in Spontaneously Hypertensive Rats

Abstract

The mechanisms by which heme oxygenase (HO) improves glucose metabolism in essential hypertension are not completely understood. Because dysfunctional insulin signaling is associated with elevated inflammation and high cholesterol and triglycerides, we investigated the effects of HO on the proinflammatory macrophage M1 phenotype and the anti-inflammatory macrophage M2 phenotype in spontaneously hypertensive rats (SHRs). SHRs are a model of human essential hypertension with features of metabolic syndrome, including impaired glucose metabolism. Spectrophotometric analysis, enzyme immunoassay, enzyme-linked immunosorbent assay, and Western immunoblotting were used. HO was enhanced with hemin or inhibited with chromium-mesoporphyrin (CrMP). Hemin suppressed inflammation by abating proinflammatory macro phage M1 phenotype (ED1) and chemokines such as macrophage chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 alpha (MIP-1α) while enhancing anti-inflammatory macrophage M2 phenotype by potentiating ED2, CD206, and CD14. Similarly, hemin improved insulin signaling by enhancing insulin receptor substrate 1 (IRS-1), IRS-2, phosphatidylinositol 3 kinase (PI3K), and glucose transporter 4 (GLUT4) but reduced total cholesterol and triglycerides. These effects were accompanied by increased HO-1, HO activity, and cyclic guanosine monophosphate (cGMP), whereas the HO inhibitor CrMP nullified the hemin effects. Importantly, the effects of the HO system on ED1, ED2, CD206, and CD14 in SHRs are novel. Hemin abated inflammation in SHRs by selectively enhancing the anti-inflammatory macrophage M2 phenotype that dampens inflammation while suppressing the pronflammatory macrophage M1 phenotype and related chemokines such as MCP-1 and MIP-1α. Importantly, the reduction of inflammation, total cholesterol, and triglycerides was accompanied by the enhancement of important proteins implicated in insulin signaling, including IRS-1, IRS-2, PI3K, and GLUT4. Thus, the concomitant reduction of inflammation, total cholesterol and triglycerides and the corresponding potentiation of insulin signaling are among the multifaceted mechanisms by which the HO system improves glucose metabolism in essential hypertension.