Peroxisome Proliferator-activated Receptor-γ Pathway Research Articles

Gabapentin attenuates cardiac remodeling after myocardial infarction by inhibiting M1 macrophage polarization through the peroxisome proliferator-activated receptor-γ pathway

ObjectivesInflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI. MethodsRats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro. ResultsIn vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-β. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1β). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1β expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages. ConclusionGabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.

Involvement of Telmisartan on the Protective Effects Mediated by the Peroxisome Proliferator-Activated Receptor-γ Pathway in Mice

Aims: The aim of this study is to further elaborate the improving effects of telmisartan on insulin resistance, beta-cell dysfunction and islet inflammation in a PPAR-γ signaling-dependent manner. Methods: The mRNA levels of renin-angiotensin system components were detected. We compared the effects of telmisartan and telmisartan combined with GW9662 (a PPAR-γ antagonist) in mice fed a high-fat diet or isolated non-diabetic mouse islets. Immunofluorescence or real-time PCR was used to determine changes in islet structure, function and inflammation as well as PPAR-γ expression. Results: Telmisartan reduced body weight, especially the visceral adipose tissue weight, which may be due to enhancing PPAR-γ expression and reshaping the RAS balance, including increased ACE2 and decreased ACE/ATR1 mRNA expression levels. IPGTT and HOMA-IR showed that telmisartan attenuated insulin resistance in a manner dependent on the duration of high-fat diet fed, which could be offset by GW9662. In addition, telmisartan normalized beta-cell function (including the increase in PDX1, GLUT2 and insulin mRNA expression levels) and islet structure (such as the maintenance of islet cell distribution, decrease in the alpha/beta ratio and alpha-cell mass and the inhibition of beta-cell apoptosis) via the activation of PPAR-γ signaling in mice fed a high-fat diet. Moreover, telmisartan inhibited the high fat diet-induced activation of p65 expression and inflammatory factors (including IL-1beta and TNF-alpha) which were stimulated by chronic palmitate exposure in pancreatic islets, while GW9662 had the reverse effect. Discussions: Our novel results exhibit critical roles for PPARγ activation in the biological effects of telmisartan and suggest a therapeutic potential for telmisartan in the prevention of type 2

Antidiabetic therapy effects on bone metabolism and fracture risk

Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-γ pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations.