Obligatory Role for Endogenous Endothelin in Mediating the Hypertrophic Effects of Phenylephrine and Angiotensin II in Neonatal Rat Ventricular Myocytes: Evidence for Two Distinct Mechanisms for Endothelin Regulation

Xia, Ying; Karmazyn, Morris

doi:10.1124/jpet.104.065185

Cited by 29 publications

(13 citation statements)

References 27 publications

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“…Overall, hypertrophic cardiomyopathy results in impairment of Ca ++ sensitivity by the myofibrils. In the present study however, we employed a model of hypertrophy induced by PE or ANGII, which involves interaction of these ligands with their cell surface receptors, GPCR [71]. The resultant intracellular response leads to increased cytosolic Ca ++ overload, which mediates a cascade of signaling pathway involving activation of PKC, which ultimately induces cardiomyocyte hypertrophy [72].…”

Section: Discussionmentioning

confidence: 99%

Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl−/HCO3 −exchanger

Sowah

Brown

Quon

et al. 2014

BMC Cardiovasc Disord

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BackgroundCardiac hypertrophy is central to the etiology of heart failure. Understanding the molecular pathways promoting cardiac hypertrophy may identify new targets for therapeutic intervention. Sodium-proton exchanger (NHE1) activity and expression levels in the heart are elevated in many models of hypertrophy through protein kinase C (PKC)/MAPK/ERK/p90RSK pathway stimulation. Sustained NHE1 activity, however, requires an acid-loading pathway. Evidence suggests that the Cl−/HCO3− exchanger, AE3, provides this acid load. Here we explored the role of AE3 in the hypertrophic growth cascade of cardiomyocytes.MethodsAE3-deficient (ae3 −/− ) mice were compared to wildtype (WT) littermates to examine the role of AE3 protein in the development of cardiomyocyte hypertrophy. Mouse hearts were assessed by echocardiography. As well, responses of cultured cardiomyocytes to hypertrophic stimuli were measured. pH regulation capacity of ae3 −/− and WT cardiomyocytes was assessed in cultured cells loaded with the pH-sensitive dye, BCECF-AM.Resultsae3 −/− mice were indistinguishable from wild type (WT) mice in terms of cardiovascular performance. Stimulation of ae3 −/− cardiomyocytes with hypertrophic agonists did not increase cardiac growth or reactivate the fetal gene program. ae3 −/− mice are thus protected from pro-hypertrophic stimulation. Steady state intracellular pH (pHi) in ae3 −/− cardiomyocytes was not significantly different from WT, but the rate of recovery of pHi from imposed alkalosis was significantly slower in ae3 −/− cardiomyocytes.ConclusionsThese data reveal the importance of AE3-mediated Cl−/HCO3− exchange in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy. Pharmacological antagonism of AE3 is an attractive approach in the treatment of cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl−/HCO3 −exchanger

Sowah

Brown

Quon

et al. 2014

BMC Cardiovasc Disord

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“…Central to the hypertrophic response is the activation of critical kinases including the mitogen-activated protein kinases (MAPKs), extracellular signal regulated kinases 1 and 2 (ERK 1 & 2), phosphatidylinositol 3-kinase (PI 3 K), protein kinase B (PKB), and the mTOR/S6 kinase system [5,24,25]. In addition, AngII's ability to induce hypertrophy appears to be facilitated by its activation of endothelins and fibroblast growth factor [26,27].…”

Section: Vascular Restenosis and Hypertrophymentioning

confidence: 98%

Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies

2007

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The renin-angiotensin-aldosterone system (RAAS) is critical in regulating systemic blood pressure, water and electrolyte balance, and pituitary gland hormones. These physiologies appear to be primarily mediated by the angiotensin II/AT(1) receptor subtype system. Overstimulation of this system can predispose cardiovascular disease (CVD) characterized by excessive vasoconstriction, fibrosis, and cardiac remodeling. If untreated, the patient typically displays a continuum of pathophysiologic conditions progressing from atherosclerosis to left ventricle hypertrophy (LVH), coronary thrombosis, myocardial infarcts, with heart failure as an endpoint. Intervention with antihypertensive therapy is necessary to inhibit this progression. RAAS blocking drugs appear to be the most effective approach. Diastolic heart failure patients benefit from treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin AT(1) receptor blockers (ARBs). Elderly CVD patients evidence age-related changes in body composition that alter the distribution and half-life of medications, thus presenting special challenges to treatment. The presence of comorbidities such as diabetes, renal dysfunction, liver insufficiency further complicates any therapeutic strategy. In addition, noncompliance because of cognitive impairment, depression, confusion due to the complexity of dose regimens, and lack of an appropriate social support system can disrupt positive outcome. The present review discusses the roles of an overactive RAAS and sympathetic nervous system as primary contributors to CVD. In addition, treatment strategies are discussed, focusing on middle aged and elderly hypertensive and heart failure patients.

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“…Excessive Ang II has deleterious effects on myocardium by a plethora of mechanisms such as increasing sarcolemmic permeability and death of cardiac myocytes or increasing permeability and destruction of coronary microvascular endothelial cells (Gavras & Gavras, 2002a). Other mechanisms include mediating oxidative stress via activation of NADPH through AT 1 3 receptor activation and the subsequent formation of ROS (Kassiri et al, 2009a) or via endothelin-1 peptide activation (Xia & Karmazyn, 2004). It has been documented that cardiac myocytes undergo hypertrophy as well as fibrosis associated with collagen production in response to Ang II both in vivo (Grobe et al, 2007) and in vitro (Wang et al, 2010).…”

Section: Angiotensin IImentioning

confidence: 99%

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

Alghamri

Weir

Anstadt

et al. 2012

J Cardiovasc Pharmacol Ther

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Mahmoud Alghamri. M.S., Department of Pharmacology and Toxicology, Wright State University, 2012. Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice.Activation of the renin angiotensin system (RAS) is a well-known driving force, governing the aggravation and progression of CVD and associated target organ damage.Angiotensin (Ang) converting enzyme 2 (ACE2), a new member within the RAS family, was first cloned from the ventricle of patient with heart failure. ACE2 was shown to be upregulated under pathological conditions. We hypothesize that loss of ACE2 negatively affects cardiac function and exacerbates hypertrophic cardiomyopathy and aortic remodeling in response to Ang II. Eight weeks old ACE2 knock out (KO) and wild type (WT) mice were infused with Ang II s.c. (1000 ng/kg/min for 4 weeks) using osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography) and cardiac/aortic structural damage (histology) were examined. At baseline before Ang II, ACE2 KO displayed a normal phenotype for cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) was increased (~40% in WT and ~33% in ACE2 KO) with no differences between groups. However, ACE2 KO responded differently to the increased MAP. Cardiac function analysis revealed severe myocardial dysfunction shown by the lowered EF% (31% vs. 13%) as well as FS% (30% vs 6%) in ACE2 KO vs WT, respectively. In addition, the cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by the increased left ventricular wall thickness as well as heart weight/ body weight ratio. Moreover, collagen staining in the myocardium and aorta revealed higher collagen percentage in ACE2 KO which indicates iv cardiovascular remodeling. Furthermore, results showed enhanced oxidative stress in the myocardium and aorta of Ang II infused ACE2 KO compared to Ang II WT. In conclusion, ACE2 attenuates myocardial maladaptive hypertrophy and cardiovascular remodeling in response to long term Ang II stimulation.v

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Obligatory Role for Endogenous Endothelin in Mediating the Hypertrophic Effects of Phenylephrine and Angiotensin II in Neonatal Rat Ventricular Myocytes: Evidence for Two Distinct Mechanisms for Endothelin Regulation

Cited by 29 publications

References 27 publications

Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl−/HCO3 −exchanger

Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl−/HCO3 −exchanger

Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

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