58 research outputs found
Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II
GPCR subtypes possess distinct functional
and pharmacological profiles,
and thus development of subtype-selective ligands has immense therapeutic
potential. This is especially the case for the angiotensin receptor
subtypes AT1R and AT2R, where a functional negative control has been
described and AT2R activation highlighted as an important cancer drug
target. We describe a strategy to fine-tune ligand selectivity for
the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl
interactions. Through this strategy an AT2R high affinity (<i>K</i><sub>i</sub> = 3 nM) agonist analogue that exerted 18,000-fold
higher selectivity for AT2R versus AT1R was obtained. We show that
this compound is a negative regulator of AT1R signaling since it is
able to inhibit MCF-7 breast carcinoma cellular proliferation in the
low nanomolar range
Addressing global disparities in blood pressure control: perspectives of the International Society of Hypertension
Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework
Angiotensin II Type 1 Receptor (AT-1R) Expression Correlates with VEGF-A and VEGF-D Expression in Invasive Ductal Breast Cancer
Mögliche Ursachen für die unbefriedigende Hypertonie-Einstellung bei Patienten der medizinischen Grundversorgung in Deutschland
Angiotensin II suppresses TNFa-induced IL-Angiotensin II über den AT2-Rezeptor verringert die durch TNFalpha induzierte Expression von Il-6 in humanen, dermalen Fibroblasten
The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.
Angiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II on endothelial growth and the role of the angiotensin receptor subtypes involved. Proliferation of rat coronary endothelial cells (CEC) and rat vascular smooth muscle cells (VSMC) was determined by [3H]thymidine incorporation, the MTT-test and by directly counting cells in a coulter counter. Angiotensin AT1- and AT2-receptors were demonstrated by binding studies and by the presence of their respective mRNA through reverse transcription polymerase chain reaction (RT-PCR). In contrast to VSMC, which in culture only express the AT1-receptor, CEC express both, AT1- and AT2-receptors simultaneously up to the third passage. Whereas ANG II stimulated growth of quiescent VSMC, an effect abolished by pretreatment with the AT1-receptor antagonist, losartan, ANG II did not induce proliferation in quiescent CEC. However, after pretreatment of quiescent endothelial cells (< passage 4) with the AT2-receptor antagonist, PD 123177, ANG II induced proliferation. This effect was reversed by additional pretreatment with losartan. ANG II significantly inhibited the proliferation of bFGF-stimulated CEC in a dose-dependent manner by maximally 50%. This effect was prevented by PD 123177 while losartan was ineffective. The AT2-receptor agonist, CGP 42112, mimicked the antiproliferative actions of ANG II, confirming the specificity of the effect. Our results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell. In coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1-receptor
The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.
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