Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARδ–STAT3 Signaling in Type 1-Like Diabetic Rats

Abstract

Ginsenoside Rh2 (Rh2) is an active principal ingredient contained in ginseng (Panax ginseng Meyer), a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ-diabetic rats), the increased fasting blood glucose levels and heart weight/body weight (HW/BW) ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor δ (PPARδ) in STZ-diabetic rats. The role of PPARδ was subsequently investigated in vitro. Rh2 restored the decreased PPARδ expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3), connective tissue growth factor (CCN2) and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARδ Taken together, PPARδ activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARδ signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis.

Molecular mechanisms regarding potassium bromate‑induced cardiac hypertrophy without apoptosis in H9c2 cells

“…Cell surface area size was determined and quantified by imaging to the complete boundary of the individual cells. The results were subsequently expressed as the percentage change of the surface area level of the cells, based on analysis using image J program, version 1.46 (National Institutes of Health, Bethesda, MD, USA; http://imagej.nih.gov/ij/) as described previously (24).…”

“…An entire field of vision was characterized using a fluorescence microscope (IX71, Olympus Corporation) connected to an imaging system (DP2-BSW, Olympus Corporation). The results were subsequently expressed as a percentage of the intracellular superoxide levels in the cells based on the analysis using image J program, version 1.46 (National Institutes of Health), as described previously (24).…”

“…As previously described (24), Total RNA was extracted from H9c2 cells using TRIzol reagent (Life Technologies; Thermo Fisher Scientific, Inc.). Total RNA (5 µg) was reverse-transcribed into cDNA with random hexamer primers (Roche Diagnostics GmbH, Mannheim, Germany).…”

Review of Ginseng Anti-Diabetic Studies

“…an STZ-induced type 1 diabetic rat model, ginsenoside Rh2 reduced fasting blood glucose and improved cardiac function via enhancing PPAR-δ signaling in diabetic rats with cardiac fibrosis [60]. In the 3T3-L1 cells, researchers that found ginsenoside F2 [68], and a ginsenosides Rg5 + Rk1 mixture [69] could reduce lipid accumulation and down-regulate expression of PPAR-γ.…”

“…Recently, Shen et al reported that Rg1 released in brain tissue using nano-drug delivery systems reduced the volume of cerebral infarction and improved neural recovery in diabetic rats with cerebral infarction [59], indicating that the hypoglycemic effect of Rg1 may be regulated through the central nervous system. Additionally, in an STZ-induced type 1 diabetic rat model, ginsenoside Rh2 reduced fasting blood glucose and improved cardiac function via enhancing PPAR-δ signaling in diabetic rats with cardiac fibrosis [60]. In the 3T3-L1 cells, researchers that found ginsenoside F2 [68], and a ginsenosides Rg5 + Rk1 mixture [69] could reduce lipid accumulation and down-regulate expression of PPAR-γ.…”