Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs
Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs
复制标题
DOI：
10.1038/s41598-020-61041-y
复制
发表时间：
2020-03-09
影响因子：
4.6
通讯作者：
Pandey, Kailash N.
中科院分区：
文献类型：
--
作者：
Arise, Kiran K.;Kumar, Prerna;Pandey, Kailash N.
两种血管活性激素，血管紧张素II（ANG II;血管收缩的）和心房利钠肽（ANP;血管舒张的）相互拮抗生物学作用。ANP通过利钠肽受体A（NPRA）起作用，降低血压和血容量。我们检验了ANG II在Npr 1（编码NPRA）的转录抑制和受体功能中起关键作用的假设。血管紧张素Ⅱ显着降低NPRA mRNA和蛋白水平和cGMP积累在培养的系膜细胞和衰减ANP介导的主动脉环离体舒张。转录因子cAMP反应元件结合蛋白（CREB）和热休克因子4a（HSF-4a）促进了ANG II对Npr 1转录的抑制作用。酪氨酸激酶（TK）抑制剂、染料木素和磷脂酰肌醇3-激酶（PI-3 K）抑制剂渥曼青霉素可逆转ANG II依赖的Npr 1转录和受体功能抑制。ANG II增强I类组蛋白去乙酰化酶（HDACs 1/2）的活性，从而降低H3 K9/14 ac和H4 K8 ac的组蛋白乙酰化。ANG II对Npr 1转录和受体信号传导的抑制作用似乎通过TK和PI-3 K途径转导，并通过CREB、HSF-4a、HDAC和修饰的组蛋白进行调节。目前的研究结果表明，ANG II介导的Npr 1转录和受体功能的抑制机制可能为治疗和预防高血压和心血管疾病提供新的分子靶点。
The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. ANP acting through natriuretic peptide receptor-A (NPRA) lowers blood pressure and blood volume. We tested hypothesis that ANG II plays critical roles in the transcriptional repression of Npr1 (encoding NPRA) and receptor function. ANG II significantly decreased NPRA mRNA and protein levels and cGMP accumulation in cultured mesangial cells and attenuated ANP-mediated relaxation of aortic rings ex vivo. The transcription factors, cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) facilitated the ANG II-mediated repressive effects on Npr1 transcription. Tyrosine kinase (TK) inhibitor, genistein and phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin reversed the ANG II-dependent repression of Npr1 transcription and receptor function. ANG II enhanced the activities of Class I histone deacetylases (HDACs 1/2), thereby decreased histone acetylation of H3K9/14ac and H4K8ac. The repressive effect of ANG II on Npr1 transcription and receptor signaling seems to be transduced by TK and PI-3K pathways and modulated by CREB, HSF-4a, HDACs, and modified histones. The current findings suggest that ANG II-mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for treatment and prevention of hypertension and cardiovascular diseases.