Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Mackasey M
PROVIDER: S-EPMC6314975 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.
| S-EPMC4447201 | biostudies-literature
Project description:Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure.Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab(-/-)/ApoE(-/-)) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59(ICAM-2+/-)/ApoE(-/-)) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-alpha/beta, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-kappaB signaling pathways.Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm.
| S-EPMC3057574 | biostudies-literature
Project description:Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe-/-) mice or control Apoe-/- mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe-/- mice had reduced accumulation of macrophages and CD4+ T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.
| S-EPMC6542846 | biostudies-literature
Project description:Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-deficient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic inflammation and macrophage infiltration. In cultured vascular smooth muscle cells (VSMCs), rAAV-mediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced inflammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferator-activated receptor (PPAR)? activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPAR? activation and anti-inflammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA.
| S-EPMC3622337 | biostudies-literature
Project description:We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-? (TGF-?) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1?. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-? and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney.
| S-EPMC3991592 | biostudies-literature
Project description:Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-beta activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-beta in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-beta activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-gamma, IL-4, IL-6, or TNF-alpha signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-beta activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-beta neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-beta in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.
| S-EPMC2810071 | biostudies-literature
Project description:UnlabelledAngiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-?/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA) and tauro-lithocholic acid-3 sulfate (TLCS), to induce apoptosis. AT-II (100 nmol/L) was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans) and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining) and necrosis (Sytox green staining) were quantified. Expression of CHOP (marker for ER stress) and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (-50%, p<0.05) without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (-50%, p<0.05). However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis).ConclusionAngiotensin II protects hepatocytes from bile salt-induced apoptosis through a combined activation of PI3-kinase, MAPKs, PKC pathways and inhibition of bile salt-induced ER stress. Our results suggest a mechanism for the observed hepatocyte-toxicity of Sartans (angiotensin receptor blockers, ARBs) in some patients with chronic liver injury.
| S-EPMC3530435 | biostudies-literature
Project description:The specialized cardiac conduction system (CCS) consists of the sinoatrial node (SAN) and the atrioventricular (AV) conduction system (AVCS), which includes proximal (AV node, bundle of His and bundle branches) and distal (Purkinje fibers) components. In four CCS marker mice [two transgenic (cGATA6|lacZ, CCS|lacZ) and two targeted gene knock-in (minK|lacZ, Hop|lacZ)] the expression of the lacZ gene (beta-gal) has been reported to mark portions of the proximal and distal AVCS; the expression of this marker in the adult SAN is unknown. The primary objective of this study was to analyze the utility of these marker mice in the identification of the SAN. Intercaval and interventricular septal regions, containing all the components of the CCS, were freshly dissected from adult mice based on the anatomical landmarks and sectioned. Immunohistochemical characterization was performed with SAN markers (Cx45, HCN4), compared to the reporter expression (beta-gal) and markers of the working myocardium (Cx40 and Cx43). In all four of the CCS marker mice, we found that beta-gal expression is consistently observed in the proximal and distal AVCS. However, the presence of lacZ gene expression in the working myocardium outside the CCS and/or the absence of this reporter expression in the SAN prevent the effective use of these mice to identify the SAN, leading us to conclude that none of the four CCS marker mice we studied specifically mark the SAN.
| S-EPMC1936434 | biostudies-literature
Project description:The respective roles of protein kinase C (PKC) and endogenous prostaglandin formation in angiotensin II (Ang II)-induced myocardial secretion of atrial natriuretic peptide (ANP) was studied in cultured, spontaneously beating, neonatal-rat cardiomyocytes. Incubation of cardiomyocytes with 0.1 microM Ang II led to a rapid but transient increase in particulate-bound PKC activity, a response accompanied by marked increases in cellular 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) generation and ANP secretion. A role for PKC in Ang II-induced 6-oxo-PGF1 alpha formation and ANP secretion was apparent, insofar as both responses were suppressed in the presence of the PKC inhibitors staurosporine (1 microM) and CGP 41251 (1 microM), as well as in cells in which PKC had been previously down-regulated by pretreatment with phorbol diester. Furthermore, Ang II-induced 6-oxo-PGF1 alpha production was found to be strongly correlated with Ang II-induced ANP release (r = 0.87, P < 0.001, n = 6), indicating a role for prostacyclin (PGI2) in Ang II-induced ANP secretion in these cells. This hypothesis was confirmed by finding that both Ang II-induced 6-oxo-PGF1 alpha production and ANP release were abolished in the presence of the respective phospholipase A2 and cyclo-oxygenase inhibitors quinacrine (10 microM) and indomethacin (10 microM), whereas exogenously applied PGI2 (1 microM) and prostaglandin E2 (0.1 microM) mimicked Ang II-induced ANP secretion in this system. Taken together, these results suggest that Ang II induces ANP secretion in spontaneously beating rat cardiomyocytes via a PKC-dependent autocrine pathway involving a cyclo-oxygenase product and a yet-to-be-identified myocardial prostanoid receptor.
| S-EPMC1137961 | biostudies-other
Project description:The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.
| S-EPMC8270920 | biostudies-literature