1.Structure-activity relationship study of angiotensin II analogs in terms of β-arrestin-dependent signaling to aldosterone production.
Valero TR1, Sturchler E2, Jafferjee M1, Rengo G3, Magafa V4, Cordopatis P4, McDonald P2, Koch WJ5, Lymperopoulos A1. Pharmacol Res Perspect. 2016 Mar 8;4(2):e00226. doi: 10.1002/prp2.226. eCollection 2016.
The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and β-arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity ("bias") toward β-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard β-arrestin-"biased" AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus β-arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for β-arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard.
2.1,25(OH)2D3 Induces Placental Vascular Smooth Muscle Cell Relaxation by Phosphorylation of Myosin Phosphatase Target Subunit 1Ser507: Potential Beneficial Effects of Vitamin D on Placental Vasculature.
Jia X, Gu Y, Groome LJ, Al-Kofahi M, Alexander JS, Li W, Wang Y. Biol Reprod. 2016 Apr 13. pii: biolreprod.116.138362. [Epub ahead of print]
Placental vascular dysfunction has been linked to insufficiency/deficiency of maternal vitamin D levels during pregnancy. In contrast, sufficient maternal vitamin D levels have shown beneficial effects on pregnancy outcomes. To study the role of vitamin D in pregnancy, we tested our hypothesis that vitamin D exerts beneficial effects on placental vasculature. We examined expression of CYP2R1, CYP27B1, vitamin D receptor (VDR), and CYP24A1 in placental vascular smooth muscle cells (VSMCs) in response to 1,25(OH)2D3 We found that VDR expression was inducible, CYP27B1 expression was dose-dependently down-regulated, and CYP24A1 expression was dose-dependently up-regulated in cells treated with 1,25(OH)2D3 These data suggest a feedback auto-regulatory system of vitamin D existing in placental VSMCs. Using VSMC/collagen-gel contraction, we evaluated the effect of 1,25(OH)2D3on placental VSMC contractility. We found that similar to losartan, 1,25(OH)2D3could diminish angiotensin II induced cell contractility.
3.Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.
Itani HA1, Dikalova AE1, McMaster WG1, Nazarewicz RR1, Bikineyeva AT1, Harrison DG1, Dikalov SI2. Hypertension. 2016 Apr 11. pii: HYPERTENSIONAHA.115.07085. [Epub ahead of print]
Vascular superoxide (O͘2 -) and inflammation contribute to hypertension. The mitochondria are an important source of O͘2 -; however, the regulation of mitochondrial O͘2 -and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines, such as interleukin 17A and tumor necrosis factor-α (TNFα) significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)-dependent mitochondrial O͘2 -production in hypertension. We tested whether CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD-/-mice prevents overproduction of mitochondrial O͘2 -in angiotensin II-infused mice, attenuates hypertension by 20 mm Hg, and improves vascular relaxation compared with wild-type C57Bl/6J mice. Treatment of hypertensive mice with the specific CypD inhibitor Sanglifehrin A reduces blood pressure by 28 mm Hg, inhibits production of mitochondrial O͘2 -by 40%, and improves vascular relaxation.
4.[Effect of Astragali Radix in improving early renal damage in metabolic syndrome rats through ACE2/Mas pathway].
Wang QY, Liang W, Jiang C, Li NY, Xu H, Yang MN, Lin X, Yu H, Chang P, Yu J. Zhongguo Zhong Yao Za Zhi. 2015 Nov;40(21):4245-50.
To study the expression of angiotensin converting enzyme 2 (ACE2) and angiotensin (Ang) 1-7 specific receptor Mas protain in renal blood vessels of metabolic syndrome ( MS) rats and its anti-oxidative effect. A total of 80 male SD rats were divided into four groups: the normal control group (NC, the same volume of normal saline), the MS group (high fat diet), the MS + Astragali Radix group (MS + HQ, 6 g x kg(-1) x d(-1) in gavage) and the MS + Valsartan group (MS + XST, 30 mg x kg(-1) x d(-1) in gavage). After four weeks of intervention, their general indexes, biochemical indexes and blood pressure were measured; plasma and renal tissue Ang II, malondialdehyde (MDA) and superoxide demutase (SOD) levels were measured with radioimmunoassay. The protein expressions of Mas receptor, AT1R, ACE and ACE2 were detected by western blot analysis. According to the result, compared with the NC group, the MS group and the MS + HQ group showed significant increases in systolic and diastolic pressures, body weight, fasting glucose, fasting insulin, triglycerides, free fatty acid and Ang II level of MS rats (P < 0.
