Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy

Abstract

Aims: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. Methods: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP–RFP–LC3. Results: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. Conclusion: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.

2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside induces autophagy of liver by activating PI3K/Akt and Erk pathway in prediabetic rats

“…This may be the one of the new evidence for the protective role of autophagy from other cell deaths, especially apoptosis. The result might be contradictory to the previous study in which TSG suppressed the mesenteric vascular autophagy in the male Zucker diabetic fatty rats by activating Akt [29]. This difference might result from a different phase of the disorder, different target organs, diverse methodology and/or experiments.…”

Adipocyte-Endothelium Crosstalk in Obesity

“…Autophagy is also crucial for endothelial cells. Obesity-induced endothelial dysfunction is associated with the upregulation of endothelial autophagy machinery ( 79 ) and vascular ceramide content ( 80 ). Exosome production and release are modified by ceramide synthesis ( 81 ), and, interestingly, adiponectin signaling in endothelial cells increased exosome secretion and reduced cellular ceramide levels ( 74 ).…”

Maternal Melatonin Therapy Attenuated Maternal High-Fructose Combined with Post-Weaning High-Salt Diets-Induced Hypertension in Adult Male Rat Offspring

“…Melatonin has been shown to activate mTOR signaling and prevent ischemic brain injury [ 30 ]. Given that mTOR regulates autophagy and that inhibition of autophagy links to hypotensive effects [ 31 , 32 ], our findings suggest that maternal melatonin therapy protects against HF/HS-induced programmed hypertension may be due to inhibition of autophagy via activation of mTOR signals, although this remains speculative.…”