Background/Aims: Hypertension is a major cause of stroke, and diabetes can increase incidence of this disease. We determined the role played by central angiotensin-(1-7) [Ang-(1-7)] pathway in modulating spontaneously hypertension with diabetic hyperglycemia. Methods: Western Blot analysis and ELISA were used to determine the protein expression of Ang-(1-7) and its signal pathway Mas-R-nNOS in the cerebral cortex and hippocampus of spontaneously hypertensive rats (SHR) and control animals. In a subset of animals, diabetic hyperglycemia was induced by systemic injection of streptozotocin (STZ). We analyzed a relationship between the levels of central Ang-(1-7) and plasma brain natriuretic peptide (BNP) indicating a risk of ischemic stroke. We further examined the effects of Ang-(1-7) on arterial blood pressure. Results: Our findings demonstrated for the first time that administration of STZ 1) attenuates the levels of Ang-(1-7) in the cerebral cortex and hippocampus, which are closely linked to plasma BNP; and 2) leads to downregulation of central Ang-(1-7)-Mas-R-nNOS pathways. Notably, STZ has greater effects in SHR. Additionally, inhibition of oxidative stress can largely improve downregulation of Ang-(1-7) in diabetic SHR. Moreover, central stimulation of Ang-(1-7) pathway or a blockade of oxidative stress improves systolic blood pressure in diabetic SHR. Conclusions: The Ang-(1-7) signaling pathway is engaged in the adaptive mechanisms associated with diabetic hypertension, suggesting that enhancing Ang-(1-7)-Mas-R-nNOS system is likely to be beneficial in preventing against cardiovascular and cerebrovascular dysfunction and vulnerability related to spontaneously hypertension, particularly to diabetic hypertension.
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. It is reported that body mass index (BMI) is risk factor for CVD. Genome-wide association studies (GWAS) have recently provided rapid insights into genetics of CVD and its risk factors. However, the specific mechanisms how BMI influences CVD risk are largely unknown. We think that BMI may influences CVD risk by shared genetic pathways. In order to confirm this view, we conducted a pathway analysis of BMI GWAS, which examined approximately 329,091 single nucleotide polymorphisms from 4763 samples. We identified 31 significant KEGG pathways. There is literature evidence supporting the involvement of GnRH signaling, vascular smooth muscle contraction, dilated cardiomyopathy, Gap junction, Wnt signaling, Calcium signaling and Chemokine signaling in CVD. Collectively, our study supports the potential role of the CVD risk pathways in BMI. BMI may influence CVD risk by the shared genetic pathways. We believe that our results may advance our understanding of BMI mechanisms in CVD.
Background and Purpose: Atherosclerosis is a common cardiovascular disease with high morbidity and mortality. It is reported to be related to oscillatory shear stress (OSS)-induced endothelial dysfunction and excessive production of inflammatory factors. Azilsartan, a specific antagonist of the angiotensin II receptor, has been approved for the management of hypertensive subjects with diabetes mellitus type II (DMII). The present study will investigate the effects of azilsartan against OSS-induced endothelial dysfunction and inflammation, as well as the underlying mechanism. Materials and Methods: Cell viability was detected using an MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were used to determine the expression levels of IL-6, TNF-α, IL-1β, VCAM-1, and ICAM-1 in human aortic endothelial cells (HAECs). Generation of reactive oxygen species (ROS) was measured using 2ʹ-7ʹdichlorofluorescin diacetate (DCFH-DA) staining, and the level of reduced glutathione (GSH) was evaluated using a commercial kit. The adhesion of THP-1 monocytes to HAECs was evaluated using calcein-AM staining. The expression level of KLF6 was determined using qRT-PCR and Western blot analysis. Results: According to the result of the MTT assay, 5 and 10 μM azilsartan were considered as the optimized concentrations applied in the present study. The elevated production of IL-6, TNF-α, and IL-1β, increased levels of ROS, decreased levels of reduced GSH, upregulated VCAM-1, ICAM-1, and E-selectin, and the aggravated adhesion of THP-1 cells to HAECs induced by OSS were all reversed by the introduction of azilsartan. The downregulation of KLF6 induced by OSS was significantly reversed by azilsartan. By knocking down the expression of KLF6, the suppressed adhesion of THP-1 cells to the HAECs, and the downregulation of VCAM-1 and ICAM-1 induced by azilsartan in OSS-stimulated HAECs were greatly reversed.Guoqian Wei, Dayong Zhu, and Yongtao Sun are co-first authors.
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