Role of thrombospondin-1 in high-salt-induced mesenteric artery endothelial impairment in rats.

The matrix glycoprotein thrombospondin-1 (THBS1) modulates nitric oxide (NO) signaling in endothelial cells. A high-salt diet induces deficiencies of NO production and bioavailability, thereby leading to endothelial dysfunction. In this study we investigated the changes of THBS1 expression and its pathological role in the dysfunction of mesenteric artery endothelial cells (MAECs) induced by a high-salt diet. Wild-type rats, and wild-type and Thbs1-/- mice were fed chow containing 8% w/w NaCl for 4 weeks. We showed that a high salt diet significantly increased THBS1 expression and secretion in plasma and MAECs, and damaged endothelium-dependent vasodilation of mesenteric resistance arteries in wild-type animals, but not in Thbs1-/- mice. In rat MAECs, we demonstrated that a high salt environment (10-40 mM) dose-dependently increased THBS1 expression accompanied by suppressed endothelial nitric oxide synthase (eNOS) and phospho-eNOS S1177 production as well as NO release. Blockade of transforming growth factor-ß1 (TGF-ß1) activity by a TGF-ß1 inhibitor SB 431542 reversed THBS1 up-regulation, rescued the eNOS decrease, enhanced phospho-eNOS S1177 expression, and inhibited Smad4 translocation to the nucleus. By conducting dual-luciferase reporter experiments in HEK293T cells, we demonstrated that Smad4, a transcription promoter, upregulated Thbs1 transcription. We conclude that THBS1 contributes to endothelial dysfunction in a high-salt environment and may be a potential target for treatment of high-salt-induced endothelium dysfunction.

Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth.

It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.

[A clinical intervention study among 463 essential hypertensive patients with metabolic syndrome].

OBJECTIVE: To study the role of baseline risk factors in predicting the onset of diabetes among essential hypertensive patients with metabolic syndrome (MS) and to evaluate an ideal therapeutic regime that could reduce the risk factors and risk of onset of diabetes. METHODS: A randomized parallel clinical trial in essential hypertensive patients of grade 1 or 2 was conducted. Two of the three components (1) increased waist circumference and/or BMI; (2) increased triglycerides (TG) and/or decreased high-density lipoprotein cholesterol; (3) impaired glucose tolerance (IGT) were present define the MS. The three intervention therapy groups were: indapamide + fosinopril (I + F, n = 151); atenolol + nitrendipine (A + N, n = 160); atenolol + nitrendipine + metformin (A + N + M, n = 152). Each case was followed-up monthly and the dosage of medicine taken be adjusted according to their BP level. The plasma glucose during fasting and two hours after taking 75 g glucose orally was also measured every six months. The new onset of diabetes was diagnosed according to the criteria. OGTT, insulin release test, lipid analysis, body weight and waist circumference were measured again at the last follow-up. RESULTS: (1) The lowering of BP was similar among the three groups (P > 0.05). 23 new diabetes onsets occurred, being 10 in group I + F and 8 in group A + N and 5 in group A + N + M, respectively (P > 0.05); (2) Proportions of patients' risk factors decreased significantly in group A + N or A + N + M, e.g. the proportions of high TG in each group reduced by 14.7% and 9.3% respectively (P < 0.05), the central fat distribution reduced by 16.7% and 15.9% respectively (P < 0.05) and the IGT reduced by 6.6% and 29.6% respectively (P < 0.05). However no changes were found in group I + F; (3) After 1 year and 5 months' follow-up, the proportions of main risk factors (high TG, central fat distribution and IGT) in the three groups were 91%, 96%, 83% and 90%, 88%, 47%, respectively. The difference of IGT was significant between two groups (P < 0.01) and the proportions of having three risk factors were 70% and 31% in the two groups (P < 0.01); (4) I + F group was better than A + N group in reduction of TG and central fat distribution. And A + N + M group improved in all risk factors. CONCLUSIONS: IGT alone or combined with increased TG plus abdominal obesity are the most important risk factors in predicting a new onset of diabetes among essential hypertensive patients with MS. Metformin in combination with atenolol plus nitrendipine can significantly prevent the onset of diabetes as well as improve patients' metabolic abnormality.