Ginkgo Biloba Leaf Extract Attenuates Atherosclerosis in Streptozotocin-Induced Diabetic ApoE-/- Mice by Inhibiting Endoplasmic Reticulum Stress via Restoration of Autophagy through the mTOR Signaling Pathway.

BACKGROUND: There is a crosstalk between endoplasmic reticulum stress (ERS) and autophagy, and autophagy could attenuate endoplasmic reticulum stress-mediated apoptosis. Ginkgo biloba leaf extract (GBE) exerts vascular protection functions. The purpose of the present study is to investigate the role of autophagy in diabetic atherosclerosis (AS) and the effect of GBE on autophagy and ERS. METHODS: Network pharmacology was utilized to predict the targets and pathways of the active chemical compounds of Gingko biloba leaf to attenuate AS. ApoE-/- mice were rendered diabetic by intraperitoneal ingestion with streptozotocin combined with a high-fat diet. The diabetic mice were divided into five groups: model group, atorvastatin group, rapamycin group, and low- and high-dose GBE groups. Serum and tissue markers of autophagy or ERS markers, including the protein expression, were examined. RESULTS: The mammalian target of rapamycin (mTOR) and NF-κB signaling pathways were targeted by the active chemical compounds of GBE to attenuate AS predicted by network pharmacology. GBE reduced the plaque area/lumen area and the plaque lipid deposition area/intimal area and inhibited the expressions of CD68, MMP2, and MMP9. Rapamycin and GBE inhibited the expression of mTOR and SQSTM1/p62 which increased in the aorta of diabetic mice. In addition, GBE reduced the expression of ERS markers in diabetic mice. GBE reduced the serum lipid metabolism levels, blood glucose, and inflammatory cytokines. CONCLUSION: Impaired autophagy and overactive endoplasmic reticulum stress contributed to diabetic atherosclerosis. mTOR inhibitor rapamycin and GBE attenuated diabetic atherosclerosis by inhibiting ERS via restoration of autophagy through inhibition of mTOR.

Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin-Induced Diabetic ApoE-/- Mice.

Diabetes was induced in high-fat diet-fed ApoE-/- mice via administration of low-dose streptozotocin (STZ) for five days. Mice were then treated with GBE (200 or 400 mg/kg) by gastric gavage daily for 12 weeks. Mice in the untreated diabetic group received saline instead, and nondiabetic C57BL/6J mice served as controls. Collagen І and ІІІ mRNA expression was measured by real-time PCR. TNF-α, IL-1ß mRNA levels, and NF-κB expression were determined to analyze intramyocardial inflammation. Hallmarks of endoplasmic reticulum stress- (ERS-) related apoptosis pathways, including phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP homologous protein (CHOP), caspase-12, and cleaved caspase-3, were analyzed by Western blotting. Diabetic ApoE-/- myocardial injury was associated with increased cardiomyocyte apoptosis (increased expression of p-JNK, CHOP, caspase-12, and cleaved caspase-3), interstitial fibrosis (increased mRNA levels of collagen І and ІІІ), and inflammation (increased mRNA levels of TNF-α and IL-1ß, and NF-κB expression). GBE at 200 and 400 mg/kg/day significantly attenuated cardiomyocyte apoptosis, collagen deposition, and inflammation in diabetic mice via inhibition of the p-JNK, CHOP, and caspase-12 pathways. Serum levels of the proinflammatory cytokines (IL-6, IL-1ß, and TNF-α), blood glucose, and lipid profiles were also regulated by GBE treatment. GBE might be beneficial in the treatment of diabetic myocardial injury.

Roles and Mechanisms of Herbal Medicine for Diabetic Cardiomyopathy: Current Status and Perspective.

Diabetic cardiomyopathy is one of the major complications among patients with diabetes mellitus. Diabetic cardiomyopathy (DCM) is featured by left ventricular hypertrophy, myocardial fibrosis, and damaged left ventricular systolic and diastolic functions. The pathophysiological mechanisms include metabolic-altered substrate metabolism, dysfunction of microvascular, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, cardiomyocyte apoptosis, mitochondrial dysfunction, and impaired Ca2+ handling. An array of molecules and signaling pathways such as p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and extracellular-regulated protein kinases (ERK) take roles in the pathogenesis of DCM. Currently, there was no remarkable effect in the treatment of DCM with application of single Western medicine. The myocardial protection actions of herbs have been gearing much attention. We present a review of the progress research of herbal medicine as a potential therapy for diabetic cardiomyopathy and the underlying mechanisms.

Cellular and Molecular Mechanisms of Diabetic Atherosclerosis: Herbal Medicines as a Potential Therapeutic Approach.

An increasing number of patients diagnosed with diabetes mellitus eventually develop severe coronary atherosclerosis disease. Both type 1 and type 2 diabetes mellitus increase the risk of cardiovascular disease associated with atherosclerosis. The cellular and molecular mechanisms affecting the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies for the prevention and treatment of diabetic atherosclerosis. In this review, we discuss progress in the study of herbs as potential therapeutic agents for diabetic atherosclerosis.