The renin–angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein-independently through β-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT1 receptor.
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- Abstract: Atherosclerosis x
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Pitchai Balakumar and Gowraganahalli Jagadeesh
S Ueda, R P Heeley, K. R Lees, H L Elliott and J M C Connell
A polymorphism of the gene encoding the human angiotensin I-converting enzyme (ACE), which is defined by an insertion/deletion polymorphism in intron 16, has been identified as a candidate genetic locus in the development of cardiovascular and renal disease.
We have demonstrated that the accuracy of ACE genotyping is critically dependent on the strategy of the PCR used in typing. Of 1238 individuals genotyped by a standard method, 335 were typed as DD, 645 as DI and 258 as II. However, when DD individuals were retyped using modified methods (including either 5% dimethyl sulphoxide, or a 'hot start') 35 of the original 335 samples (10·5%) were retyped as DI.
In approximately half of these mistyped samples, PCR amplification was assessed as inefficient by the absence of a third faint heteroduplex band in a control ID sample: when the assay was repeated without any modifications, the mistyped samples were correctly genotyped. In the remainder, mistyping persisted. In these cases, the use of a third 'nested' PCR primer specific for the I allele was required for successful genotyping, providing a more reliable strategy without the need for further modification to the PCR technique. Our results suggest that the triple primer approach is the method of choice for accurate ACE genotyping.
Andreas Hoeflich and Maximilian Bielohuby
The adrenal gland influences a multitude of processes during stress response, but also potently affects the immune system, glucose metabolism, electrolyte or water homeostasis, and cardiovascular functions. According to the present understanding, the adrenal cortex is tightly controlled by the hypothalamic–pituitary–adrenal axis. This axis involves hypothalamic CRH and pituitary ACTH which determine processes of adrenocortical growth and function. However, control of the adrenal gland comprises a plethora of additional endogenous or exogenous factors. Among those are diverse hormones, psychosocial parameters, physiological stress, secondary plant products, or even environmental pollutants. In the present review, we summarize the current view of endocrine growth control in the adrenal gland. We then discuss intracellular mechanisms of adrenal growth control and focus on extracellular signal regulated kinases 1/2 (ERK1/2), which have been demonstrated to be controlled by not only ACTH or angiotensin II, but also by a large number of additional effectors. On the basis of these multiple exogenous or endogenous factors which impact on the adrenal gland through ERK1/2 activity, we speculate on a mechanism by which ERK1/2 act as a central integrative growth regulatory elements in the adrenal gland.
Ray-Jade Chen, His-Chin Wu, Mu-Hsin Chang, Chao-Hung Lai, Yun-Chen Tien, Jin-Ming Hwang, Wu-Hsien Kuo, Fuu-Jen Tsai, Chang-Hai Tsai, Li-Mien Chen, Chih-Yang Huang and Chun-Hsien Chu
This study examines the role of IGF2/mannose 6-phosphate receptor (IGF2R) signaling in the signaling transduction regulation and cell apoptosis in H9c2 cardiomyoblast cells. However, it is difficult to recognize the distinct activation of IGF2 signaling without interfacing with IGFI receptor (IGF1R) after exposure to IGF2. Leu27IGF2, an analog of IGF2 that interacts selectively with the IGF2R, was used to specifically activate IGF2R signaling in this study. DNA fragmentation and TUNEL assay revealed that in contrast to IGF1 treatment preventing angiotensin II and AG1024-induced cell apoptosis, Leu27IGF2 appears to synergistically increase apoptosis in those cells. We further found cell apoptosis induction and an increase in the active form of caspase 3 in the treatment of cells with Leu27IGF2, but not IGF1. To detect the interaction between IGF2R and Gαq using the immunoprecipitation assay, we found that IGF2R could directly interact with Gαq and after treatment with Leu27IGF2 the binding ability of Gαq to IGF2R had increased. This sequentially resulted in the phosphorylation of phospholipase C-β, a key downstream modulator of Gαq, on serine 537. Moreover, disruption of the Gαq protein by small interferon RNA reduced the cell apoptosis induced by Leu27IGF2. Our findings demonstrate that IGF2R activation appears to induce cell apoptosis via Gαq-deriving signaling cascades and its effect is completely different from IGF1R survival signaling.
Ying Xing, Jingbo Lai, Xiangyang Liu, Nana Zhang, Jie Ming, Hengxin Liu and Xi Zhang
Diabetic foot ulceration (DFU) represents a common vascular complication of diabetes mellitus (DM) with high morbidity and disability resulting from amputation. Netrin-1 level was decreased in type 2 DM patients and has been identified as a protective regulator against diabetes-triggered myocardial infarction and nephropathy. Unfortunately, its role and molecular mechanism in DFU remain poorly elucidated. Here, netrin-1 levels were reduced in DM and DFU patients relative to healthy controls, with netrin-1 levels being the lowest in DFU patients. Moreover, exposure to high glucose (HG) also suppressed netrin-1 expression in human umbilical vein endothelial cells (HUVECs). Elevated netrin-1 expression by infection with Ad-netrin-1 adenovirus vector protected against HUVEC injury in response to HG by ameliorating the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, cell apoptotic rate and caspase-3 activity. Importantly, HG-impaired angiogenesis was improved after netrin-1 overexpression by elevating cell migration, capillary-like tube formation and VEGF production. Mechanism assay substantiated that netrin-1 elevation increased the phosphorylation levels of AKT and eNOS, and NO production, which was notably suppressed by HG, indicating that netrin-1 overexpression restored HG-triggered impairment of the PI3K/AKT-eNOS pathway. More intriguingly, preconditioning with LY294002 (PI3K/AKT antagonist) or N G-monomethyl-l-arginine (eNOS inhibitor) antagonized netrin-1-induced activation of the PI3K/AKT-eNOS pathway. Concomitantly, treatment with these antagonists also attenuated the protective role of netrin-1 in endothelial dysfunction upon HG stimulation. These results suggest that elevation of netrin-1 may restore HG-triggered impairment of HUVEC and angiogenesis by activating the PI3K/AKT-eNOS pathway, indicating a potential agent for wound healing in DFU patients.
MH Bassett, Y Zhang, C Clyne, PC White and WE Rainey
11beta-Hydroxylase (hCYP11B1) and aldosterone synthase (hCYP11B2) are closely related isozymes with distinct roles in cortisol and aldosterone production respectively. Aldosterone synthase catalyzes the final step in aldosterone biosynthesis and is expressed only in the zona glomerulosa of the normal adrenal. 11beta-Hydroxylase catalyzes the final reaction in the production of cortisol and is expressed at higher levels in the zona fasciculata. The mechanisms causing differential expression of these genes are not well defined. Herein, we demonstrate contrasting roles for the orphan receptor steroidogenic factor-1 (SF-1) in the regulation of human (h) CYP11B1 and hCYP11B2. Human NCI-H295R (H295R) or mouse Y-1 cells were transiently transfected with luciferase reporter constructs containing 5'-flanking regions of hCYP11B1, hCYP11B2, human 17alpha-hydroxylase (hCYP17), human cholesterol side-chain cleavage (hCYP11A1) or mouse (m) cyp11b2 (mcyp11b2). Co-transfection of vectors encoding SF-1 increased expression of hCYP11B1, hCYP11A1 and hCYP17 constructs, but inhibited hCYP11B2 reporter activity. Murine, bovine and human SF-1 were unable to increase transcription of hCYP11B2 in H295R cells. Both hCYP11B2 and mcyp11b2 promoter constructs were inhibited similarly by human SF-1. In mouse Y-1 cells, reporter expression of hCYP11B2 and mcyp11b2 was very low compared with hCYP11B1 constructs, suggesting that this adrenal cell model may not be appropriate for studies of CYP11B2. Electrophoretic mobility shift assay demonstrated that SF-1 interacted with an element from both hCYP11B1 and hCYP11B2. However, mutation of this element, termed Ad4, did not prevent agonist stimulation of hCYP11B2 by angiotensin II or forskolin but blocked activity of hCYP11B1. In some, but not all, reports of genetic linkage analysis, a naturally occurring single nucleotide polymorphism within the Ad4 element of hCYP11B2 (-344C/T) has been associated with cardiovascular disease. Herein, we have demonstrated that this polymorphism influenced binding of SF-1 in electrophoretic mobility shift assays, with the C allele binding SF-1 more strongly than the T allele. However, when hCYP11B2 constructs containing these alleles were transfected into H295R cells, there was no difference in agonist-stimulated expression or the response of either reporter construct to co-expression with human SF-1. Taken together, these data suggest that SF-1 and the Ad4 element are not major regulators of adrenal hCYP11B2 gene expression. Thus far, hCYP11B2 is the first steroid hydroxylase gene which is not positively regulated by SF-1.
Emma J Agnew, Jessica R Ivy, Sarah J Stock and Karen E Chapman
Glucocorticoids are essential in mammals to mature fetal organs and tissues in order to survive after birth. Hence, antenatal glucocorticoid treatment (termed antenatal corticosteroid therapy) can be life-saving in preterm babies and is commonly used in women at risk of preterm birth. While the effects of glucocorticoids on lung maturation have been well described, the effects on the fetal heart remain less clear. Experiments in mice have shown that endogenous glucocorticoid action is required to mature the fetal heart. However, whether the potent synthetic glucocorticoids used in antenatal corticosteroid therapy have similar maturational effects on the fetal heart is less clear. Moreover, antenatal corticosteroid therapy may increase the risk of cardiovascular disease in adulthood. Here, we present a narrative review of the evidence relating to the effects of antenatal glucocorticoid action on the fetal heart and discuss the implications for antenatal corticosteroid therapy.
Angela Nebbioso, Carmela Dell'Aversana, Anne Bugge, Roberta Sarno, Sergio Valente, Dante Rotili, Fabio Manzo, Diana Teti, Susanne Mandrup, Paolo Ciana, Adriana Maggi, Antonello Mai, Hinrich Gronemeyer and Lucia Altucci
Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects, and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II, and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle and neuronal differentiation. Here, we show that the novel class II-selective inhibitor MC1568 interferes with the RAR- and peroxisome proliferator-activated receptor γ (PPARγ)-mediated differentiation-inducing signaling pathways. In F9 cells, this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-Luc mice, we find that MC1568 impairs PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.
SM MacKenzie, CJ Clark, R Fraser, CE Gomez-Sanchez, JM Connell and E Davies
The terminal stages of cortisol and aldosterone production in the human adrenal gland are catalysed by the enzymes 11beta-hydroxylase and aldosterone synthase, which are encoded by the CYP11B1 and CYP11B2 genes respectively. Recent studies have suggested that aldosterone and cortisol are also made in other tissues such as the brain, heart and vascular system and may play a role in cardiovascular homeostasis. The aim of this study was to confirm the presence of these enzymes and localise them precisely in the rat brain. Reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting confirmed transcription of CYP11B1 and CYP11B2 in whole brain and hypothalamus minces from Wistar-Kyoto rats. 11beta-Hydroxylase and aldosterone synthase were immunolocalised in paraffin-embedded rat adrenal and brain sections using mouse monoclonal antibodies. Negative controls utilised a mouse monoclonal antibody raised against a non-mammalian epitope. In the brain, 11beta-hydroxylase and aldosterone synthase were detected in the cerebellum, especially the Purkinje cells, as well as the hippocampus. The specificities of the 11beta-hydroxylase and aldosterone synthase antibodies were confirmed by positive immunostaining of the relevant regions of the adrenal cortex. This is the first direct evidence that steroid hydroxylases involved in the final stages of corticosteroid biosynthesis are present in specific regions of the central nervous system.
Jéssyca Aparecida Soares Giesen, Wender do Nascimento Rouver, Eduardo Damasceno Costa, Virgínia Soares Lemos and Roger Lyrio dos Santos
Progesterone seems to play a role in cardiovascular physiology since its receptors are expressed on endothelial cells from both sexes of mammals. However, little is known about its role on the coronary circulation. Thus, this study aims to evaluate the effect of acute administration of progesterone on the coronary bed and the endothelial pathways involved in this action in normotensive rats of both sexes. A dose–response curve of progesterone (1–50 μmol/L) in isolated hearts using the Langendorff preparation was performed. Baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effect of progesterone was evaluated before and after infusion with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, catalase, and Tiron. The analysis of nitric oxide (NO) and superoxide anion (O2 · −) was performed by DAF-2DA and DHE, respectively. Female group showed higher CPP. Nevertheless, progesterone promoted a similar relaxing response in both sexes. The use of L-NAME increased vasodilatory response in both sexes. When indomethacin was used, only the males showed a reduced relaxing response, and in the combined inhibition with L-NAME, indomethacin, and catalase, or with the use of Tiron, only the females presented reduced responses. NO and O2 ·− production has increased in female group, while the male group has increased only NO production. Our results suggest that progesterone is able to modulate vascular reactivity in coronary vascular bed with a vasodilatory response in both sexes. These effects seem to be, at least in part, mediated by different endothelial pathways, involving NO and EDH pathways in females and NO and prostanoids pathways in males.