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Identifications of potential therapeutic targets and drugs in angiotensin II-induced hypertension.

ABSTRACT: This study aimed to identify the underlying therapeutic targets of angiotensin II (AngII)-induced hypertension, and screen the related drugs.The gene expression profiles of GSE93579 and GSE75815 were used to identify differentially expressed genes (DEGs) between AngII-induced hypertension and control samples based on meta-analysis. These DEGs were analyzed using Gene-Ontology (GO) function and pathway enrichment methods. Subsequently, the weighed gene coexpression network analysis (WGCNA)-based meta-analysis was applied to determine transcriptional signature with DEGs. Additionally, the functions of the modules were analyzed based on the network, and miRNAs were identified. Finally, small molecule drugs correlation with DEGs was identified.In total, 346 upregulated DEGs (e.g., Rgs7?bp) and 360 downregulated DEGs (e.g., Ebf3) were identified between AngII and control samples. In addition, a total of 150 DEGs in the brown, red, and yellow modules with higher correlation coefficient according to WGCNA, were used to construct the coexpression network, including Rgs7?bp and Ebf3, etc. in brown modules. Besides, 3 modules were obtained after the functions of the modules analysis. Moreover, 5 miRNAs were integrated in modules, including miR-124A, miR-524, miR-493, miR-323, and miR-203. Finally, anisomycin was the highest correlation with DEGs.MiR-124a might be involved in the pathogenesis of hypertension via targeting Ebf3 and Rgs7?bp, which possibly represent a novel and effective strategy for treatment of hypertension. Anisomycin might be performed to reduce blood pressure by blocking MAPK signaling pathway.

SUBMITTER: Wu X

PROVIDER: S-EPMC5704797 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identifications of potential therapeutic targets and drugs in angiotensin II-induced hypertension.

Wu Xiaoli X Fan Ruihua R

Medicine 20171101 46

This study aimed to identify the underlying therapeutic targets of angiotensin II (AngII)-induced hypertension, and screen the related drugs.The gene expression profiles of GSE93579 and GSE75815 were used to identify differentially expressed genes (DEGs) between AngII-induced hypertension and control samples based on meta-analysis. These DEGs were analyzed using Gene-Ontology (GO) function and pathway enrichment methods. Subsequently, the weighed gene coexpression network analysis (WGCNA)-based ...[more]

PMID: 29145252

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Project description:Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7?kinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7?kinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7?kinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7?kinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7?kinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7?kinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7?kinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage.

Dataset Information

Identifications of potential therapeutic targets and drugs in angiotensin II-induced hypertension.

Publications

Identifications of potential therapeutic targets and drugs in angiotensin II-induced hypertension.

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