Tetrahydroxystilbene glycoside improves endothelial dysfunction and hypertension in obese rats: The role of omentin-1.

RATIONALE: Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT-/-) mice were used. In vitro, human umbilical vein endothelial cells (HUVECs) and mature adipocytes differentiated from human visceral preadipocyte (HPA-v) were maintained in a co-culture system. RESULTS: TSG was the main active component of PMT reducing systolic blood pressure and improving endothelial vasodilation. Fortnight-TSG treatment (100 mg/kg/day) increased serum omentin-1 level, also activated Akt/eNOS signaling and enhanced NO bioactivity; decreased expression of NOX2 and p22phox, suppressed production of superoxide and peroxynitrite anion. OMT-/- mice showed elevated blood pressure and impaired endothelial vasorelaxation, whereas hypotensive effect of TSG was blunted. In co-culture system, TSG incubation promoted binding of peroxisome proliferator-activated receptor-γ (PPAR-γ) and Itln-1 promoter in adipocytes, activated Akt/eNOS/NO signaling and attenuated oxidative/nitrative stress in HUVECs. Suppression of Itln-1 with siRNA significantly blocked the protective effect of TSG in vitro. CONCLUSIONS: Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.

Tetrahydroxystilbene Glucoside Inhibits Excessive Autophagy and Improves Microvascular Endothelial Dysfunction in Prehypertensive Spontaneously Hypertensive Rats.

Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension.

Apocynum venetum leaf attenuates myocardial ischemia/reperfusion injury by inhibiting oxidative stress.

Apocynum venetum, a Chinese medicinal herb, is reported to be neuroprotective. However, whether Apocynum venetum leaf extract (AVLE) protects against ischemic myocardium remains elusive. Our present study was aimed to observe the effects of AVLE preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to investigate the possible mechanisms. Rats were treated with AVLE (500 mg/kg/d, o.g.) or distilled water once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. AVLE preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, AVLE reduced infarct size, plasma creatine kinase (CK)/lactate dehydrogenase (LDH) activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, AVLE preconditioning significantly inhibited superoxide generation, gp91(phox) expression, malonaldialdehyde formation and enhanced superoxide dismutase (SOD) activity in I/R hearts. Furthermore, AVLE treatment increased Akt and extracellular regulated protein kinases 1/2 (ERK1/2) phosphorylations in I/R rat heart. Either the Phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin or the ERK1/2 inhibitor PD98059 blocked AVLE-stimulated anti-oxidative effects and cardioprotection. Our study demonstrated for the first time that AVLE reduces oxidative stress and exerts cardioprotection against MI/R injury in rats.

Semen cassiae attenuates myocardial ischemia and reperfusion injury in high-fat diet streptozotocin-induced type 2 diabetic rats.

Obese patients with type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, are liable to more severe myocardial infarction. Semen Cassiae is proven to reduce serum lipid levels. This study investigated whether the Semen Cassiae extract (SCE) reduces myocardial ischemia and reperfusion (MI/R) injury with or without diabetes and the underlying mechanisms. The high-fat diet-fed streptozotocin (HFD-STZ) rat model was created as a T2DM model. Normal and DM rats received SCE treatment orally (10 mg/kg/day) for one week. Subsequently these animals were subjected to MI/R. Compared with the normal animals, DM rats showed increased plasma total cholesterol (TC) and triacylglycerol (TG), and more severe MI/R injury and cardiac functional impairment. SCE treatment significantly reduced the plasma TC and TG, improved the instantaneous first derivation of left ventricle pressure and reduced infarct size, decreased plasma creatine kinase and lactate dehydrogenase levels, and apoptosis index at the end of reperfusion in diabetic rats. Moreover, SCE treatment increased the antiapoptotic protein Akt and ERK1/2 phosphorylation levels. Pretreatment with a PI3K inhibitor wortmannin or an ERK1/2 inhibitor PD98059 not only blocked Akt and ERK1/2 phosphorylation respectively, but also inhibited the cardioprotective effects of SCE. However, SCE treatment did not show any effects on the MI/R injury in the normal rats. Our data suggest that SCE effectively improves myocardial function and reduces MI/R-induced injury in diabetic but not normal animals, which is possibly attributed to the reduced TC/TG levels and the triggered cell survival signaling Akt and ERK1/2.

Alpha-linolenic acid intake prevents endothelial dysfunction in high-fat diet-fed streptozotocin rats and underlying mechanisms.

BACKGROUND: Endothelial dysfunction is an important factor in the pathogenesis of diabetes related vascular complications, and acute alpha-linolenic acid (ALA) intake can increase flow-mediated dilation of the diabetic artery at 4 h postprandially. However, whether chronic ALA supplementation may prevent endothelial dysfunction in the process of diabetes and underlying mechanisms remains largely unknown. MATERIALS AND METHODS: The high-fat diet-fed streptozotocin (HFD-STZ) rats provided an animal model for T2DM. Age-matched normal and HFD-STZ rats randomly received normal diet or ALA (500 mg/kg per day). After 5 weeks of feeding, endothelial function was determined. RESULTS: Diabetes caused significant endothelial dysfunction (maximal vasorelaxation responses to ACh) in aortic segments, and ALA intake alleviated endothelial dysfunction. Superoxide production and peroxynitrite (ONOO-) formation were reduced with ALA supplement in diabetic vascular segments. Interestingly, ALA intake enhanced eNOS but inhibited iNOS activity in diabetic vessels. Moreover, ALA intake significantly increased eNOS phosphorylation. On the other hand, gp91phox and iNOS overexpression were reduced moderately with ALA intake in diabetic vessels. CONCLUSIONS: We concluded that ALA prevents diabetes-induced endothelial dysfunction by enhancing eNOS activity and attenuates oxidative/nitrative stress by inhibiting iNOS and NADPH oxidase expression and ONOO- production.

Achyranthes bidentata polypeptides reduces oxidative stress and exerts protective effects against myocardial ischemic/reperfusion injury in rats.

Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP) preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to test the possible mechanisms. Rats were treated with ABPP (10 mg/kg/d, i.p.) or saline once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. ABPP preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, ABPP reduced infarct size, plasma creatine kinase (CK)/lactate dehydrogenase (LDH) activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, ABPP preconditioning significantly inhibited superoxide generation, gp91phox expression, malonaldialdehyde formation and enhanced superoxide dismutase activity in I/R hearts. Furthermore, ABPP treatment inhibited PTEN expression and increased Akt phosphorylation in I/R rat heart. PI3K inhibitor wortmannin blocked Akt activation, and abolished ABPP-stimulated anti-oxidant effect and cardioprotection. Our study demonstrated for the first time that ABPP reduces oxidative stress and exerts cardioprotection against MI/R injury in rats. Inhibition of PTEN and activation of Akt may contribute to the anti-oxidant capacity and cardioprotection of ABPP.

Searching for phytoinsulins as cardiovascular protector in metabolic syndrome.

Metabolic syndrome is well known to increase the risk of cardiovascular disease and diabetes. As the key feature of metabolic syndrome, insulin resistance occurs when target tissues cannot respond properly to insulin and develops in multiple organs, including the vasculature and heart. Accumulating evidence has suggested insulin-induced PI3K-Akt-eNOS survival signaling as a potent therapeutic target for cardiovascular disorders and highlighted the impaired survival signaling as a key link between insulin resistance and cardiovascular disease. However, long-term insulin treatment is inconvenient and may increase the risk of hypoglycemia. More importantly, the effects of insulin are significantly blunted in patients with insulin resistance due to the pathway-specific impairment of PI3K-Akt signaling, and exogenous chronic insulin administration may lead to the over-activation of Ras-MAPK signaling which may result in unwanted side effects. Our recent study has shown that some Chinese medicinal herbs can directly activate PI3K-Akt-eNOS survival signals and improve tissue insulin sensitivity to exert endothelial and cardiac protective effects in diabetic animals. These herbs or phytoinsulins as we named, targeting insulin-activated cell survival signals and exert insulin-like actions, have promising beneficial effects on prevention and treatment of diabetes- and insulin resistance-induced cardiovascular disorders. Another advantage of phytoinsulins is that they generally exert multiple actions, including mild blood glucose-lowering effect, pancreatic ß cells protection and adipogenesis reduction, for better cardiovascular protection. In this review, we discussed our strategies of searching for phytoinsulins and their potential beneficial effects in the treatment of metabolic syndrome, especially their values in prevention of diabetic cardiovascular disease.