Background and purpose: Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity. Experimental approach: After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic b-galactosidase staining. The bromo-deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting. Key results: Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre-treatment with the PI3K inhibitor, LY294002, significantly attenuated resveratrol-induced telomerase activity. Conclusions and implications:Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K-Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.

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Summary. Background and objective: Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia miltiorrhiza Bunge, a herb that is widely used for atherothrombotic disease treatment in Asian medicine. As platelets play pivotal roles in atherothrombogenesis, we studied the effect of SAA on platelet activation and its underlying mechanisms. Methods and Results: SAA dose-dependently inhibited platelet aggregation induced by ADP, thrombin, collagen and U46619. It reduced ADP-enhanced platelet P-selectin expression and fibrinogen binding, which consequently hampered ADPinduced platelet-leukocyte aggregation. SAA also inhibited platelet spreading on fibrinogen, a process mediated by outsidein signaling. Under an arterial shear rate of 1000 s , SAA decreased platelet adhesion on collagen surfaces by 40%. Western blot analysis showed that SAA, like the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and TGX-221, potently inhibited PI3K, as shown by reduced Akt phosphorylation. The in vitro findings were further evaluated in the mouse model of arterial thrombosis, in which SAA prolonged the mesenteric arterial occlusion time in wild-type mice (35 ± 2 min without SAA and 56 ± 4 min with SAA; P < 0.01). Interestingly, SAA could even counteract the shortened arterial occlusion time in Ldlr tm1Her mutant mice (21 ± 2 min without SAA and 45 ± 4 min with SAA; P < 0.01). Conclusions: SAA inhibits platelet activation via the inhibition of PI3K, and attenuates arterial thrombus formation in vivo. Our data suggest that SAA may be developed as a novel therapeutic agent for the prevention of thrombotic disorders.

Background and purposeCardiovascular diseases and dementia are two major diseases in the elderly. Atherosclerosis is associated with future vascular events and cognitive impairment. The PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study is a population-based prospective cohort study with comprehensive evaluation of multiterritorial artery stenosis and plaque using advanced vascular imaging techniques and prospective collection of vascular events and cognitive assessments.MethodsBetween May 2017 and September 2019, the PRECISE study enrolled 3067 community-dwelling adults with ages between 50 and 75 years cluster sampled from six villages and four communities of Lishui city in China. Data are collected in face-to-face interviews at baseline, 2-year and 4-year follow-up visits. Brain MRI including high-resolution sequences for intracranial and carotidal arteries and CT angiography for thoracoabdominal arteries were performed at baseline and will be rescanned after 4 years. Cardiovascular/cerebrovascular events and cognitive assessment will be prospectively collected after the enrollment. Blood and urine samples were collected and biomarkers were tested at baseline.ResultsA total of 3067 subjects were enrolled, among which 53.5% were female with an average age of 61.2±6.7 years. Among them, 2.8%, 8.1%, 43.1% and 21.6% had a history of stroke, coronary heart diseases, hypertension and diabetes mellitus, respectively.ConclusionsThe PRECISE study is a population-based prospective cohort study with comprehensive evaluation of atherosclerotic stenosis and plaque using advanced vascular imaging techniques. Data from this cohort provide us an opportunity to precisely evaluate polyvascular atherosclerosis and its association with future vascular events and cognitive impairment.Trial registration numberClinicalTrials.gov Registry (NCT03178448).

Aims: To investigate the value of B-type natriuretic peptide (BNP) in diagnosing left ventricular diastolic dysfunction in patients with hypertension. Methods: The left ventricular diastolic function and plasma BNP levels were assessed prospectively in 135 hypertensive patients. Results: The plasma BNP in patients with (n=61) and without (n=74) diastolic dysfunction was 122F105 and 18F16 pg/ml, respectively ( p<0.001). Increased BNP levels were associated with systolic blood pressure ( p<0.05), left ventricular mass index ( p<0.001), the E/A ratio of transmitral flow ( p<0.01) and the isovolumic relaxation time ( p<0.01). A receiver-operator characteristic curve showing the sensitivity and specificity of BNP against the echocardiography diagnosis of diastolic dysfunction revealed an area under the curve (accuracy) of 0.904 ( p<0.01). Using a cut-off value of >40 pg/ml, the sensitivity and specificity of plasma BNP in diagnosing left ventricular diastolic dysfunction were 79% and 92%, respectively. Conclusions: The plasma BNP levels in patients with hypertension are closely related to left ventricular hypertrophy and filling impairment. Plasma BNP may be used to facilitate the diagnosis of left ventricular diastolic dysfunction.

SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy.

Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33 mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-κB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20 mg/kg/day for 8 weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-κB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-κB in DCM, indicating that they may be important therapeutic targets for diabetic complications.