As a major amino acid, glycine has multiple functions in metabolism, growth, immunity, cytoprotection, and survival. The aim of this study was to determine the effects of glycine on pathologic cardiac hypertrophy and the mechanism underlying it. Pre-treatment with glycine significantly attenuated murine cardiac hypertrophy induced by transverse aortic constriction or by administration of angiotensin II (Ang II). This action was associated with a suppressive extracellular signal-regulated kinase 1/2 phosphorylation in myocardium. The cardioprotective effect of glycine disappeared when endogenous glycine receptor α2 was knocked down by mRNA interference in rats. Co-culture experiments revealed that glycine could also antagonize Ang II stimulated release of transforming growth factor β and endothelin-1 by cardiomyocytes, which prevented an over-production of collagens in rat fibroblasts. These results, for the first time, demonstrate that glycine may be a novel cardioprotector against pressure overload induced cardiac hypertrophy. Thus, glycine would be useful in the prevention of cardiac hypertrophy and heart failure.

BACKGROUND AND PURPOSE:It has been accepted that AMPK (Adenosine monophosphate-activated protein kinase) activation exhibits many beneficial effects on glucolipid metabolism. Lysophosphatidylcholine (LPC) is an important lysophospholipid which can improve blood glucose levels in diabetic mice and attenuate inflammation by activating AMPK signal pathway in macrophages. Synthetic alkylphospholipids (ALPs), such as miltefosine, is used as an alternate of LPC for the clinical application. Here, we investigated whether miltefosine could have an impact on hepatic steatosis and related metabolic disorders.EXPERIMENTAL APPROACH:Mice were fed with high fat diet (HFD) for 16 weeks to generate an obese model. Next, the obese mice were randomly divided into three groups: saline-treated and miltefosine-treated (2.5 or 5 mg/kg/d) groups. Miltefosine was intraperitoneally administrated into mice for additional 4 weeks plus HFD treatment.KEY RESULTS:It was shown that miltefosine treatment could substantially improve glucose metabolism, prevented hepatic lipid accumulation, and inhibited liver inflammation in HFD-fed mice by activating AMPK signal pathway. In vitro, miltefosine stimulated AMPKα phosphorylation both in time and dose dependent manner and decreased lipid accumulation in liver cells. When a specific AMPK inhibitor compound C was used to treat mice, the antagonistic effects of miltefosine on HFD-induced mouse hyperlipidaemia and liver steatosis were abolished. Treatment with miltefosine also dramatically inhibited the HFD-induced liver inflammation in mice.CONCLUSIONS AND IMPLICATIONS:Here we demonstrated that miltefosine might be a new activator of AMPK signal pathway in vivo and in vitro and be useful for treatment of hepatic steatosis and related metabolic disorders.

Class A scavenger receptor (SR-A) is a multifunctional molecule that participates in macrophage-mediated inflammation. Here we evaluated the role of SR-A in angiotensin II (Ang II)-induced hypertensive vascular remodeling. Chronic infusion of Ang II leads to an increased systolic blood pressure both in SR-A knockout (SR-A−/−) and wild type (SR-A+/+) mice with no significant difference between these two groups. SR-A−/− hypertensive mice, however, exhibited a marked augmentation of arterial wall thickening and vascular cell proliferation compared with SR-A+/+ hypertensive mice. M1 macrophage markers were increased whereas M2 macrophage markers were decreased in vascular tissues of SR-A−/− mice. Co-culture experiments revealed that more pro-inflammatory cytokines like TNF-α were produced by SR-A−/− peritoneal macrophages leading to a stronger proliferation of primary vascular smooth muscle cells in vitro. In addition, SR-A−/− macrophages were more prone to lipopolysaccharide-induced M1 differentiation while resisting interleukin-4-induced M2 differentiation. Importantly, transplantation of SR-A−/− bone marrow into SR-A+/+ mice significantly augmented Ang II-induced vascular remodeling. These results show that SR-A is critical for Ang II-induced vascular remodeling by regulating macrophage polarization. Therefore, SR-A may be a useful therapeutic target for the intervention of hypertensive vascular remodeling.