Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

Sopel, Mryanda; Rosin, Nicole L.; Lee, Timothy Dg G.; Légaré, Jean‐François

doi:10.1038/labinvest.2010.190

Cited by 65 publications

(124 citation statements)

References 41 publications

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“…Moreover, in Dahl salt-sensitive hypertensive rats the up-regulation of ACE, AT1R and nuclear factor--B (NF-B) was inhibited by apelin-13 treatment [111]. These results confirm the hypothesis that RAS and NF-B can lead to cardiac fibrosis and remodelling [113][114][115].…”

Section: Protection Against Cardiac Remodellingsupporting

confidence: 61%

Effects of apelin on the cardiovascular system

et al. 2015

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Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterised by different numbers of aminoacids. The number of aminoacids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin, can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes of apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long lasting (6 hours) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling. KeywordsApelin/APJ system, heart failure, ischemia-reperfusion injury, contractility, cardiac protection, Reninangiotensin system 2 The apelin/APJ system Apelin In 1998 Tatemoto et al. discovered the endogenous peptide capable of binding the G protein-coupled receptor (GPCR) APJ [1,2], which at that time was considered an orphan receptor becaue its ligand was unknown. The just discovered ligand was called, apelin e.g APj Endogenous LIgaNd. Apelin is expressed in hearts, lungs, kidneys, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma. The gene of apelin is located on chromosome X [3] and encodes a 77 aminoacid sequence called pre-pro-apelin [4]. Upon cleavage by a family of endopeptidases, pre-pro-apelin generates several C-terminal fragments of various size, which are classified on the basis of the number of aminoacids. The active isoforms range from 36 to 12 aminoacids. As fragments shorter than 12 aminoacids are biologically inactive, it appears evident that the Cterminal 12 aminoacids are essential for receptor binding, whereas the N-terminal sequence modulates the interaction with the receptor [5]. At present it is recognized that, although different isoforms display similar functions, active isoforms differ in tissue distribution, potency and receptor binding affinity [6]. Apelin-13 and, to a lesser extent, apelin-36 have been considered the most active isoforms with the greatest activity on the cardi...

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Section: Protection Against Cardiac Remodellingsupporting

confidence: 61%

Effects of apelin on the cardiovascular system

et al. 2015

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“…We have shown that animals exposed to AngII develop hypertension and early infiltration (1 day) by fibroblast progenitor cells known as fibrocytes. 17 We and others have also provided evidence that strategies to limit the migration of fibrocytes inhibit the development of fibrosis, supporting an effector role for these cells.…”

Section: Introductionmentioning

confidence: 73%

“…A blinded observer quantified the infiltrating cells by counting the number of grids affected within an image of an entire heart cross-section at Â5 magnification (one section per animal), based on a previously published gridscoring method to quantify the degree of cellular infiltration between groups. 17 …”

Section: Histological Analysismentioning

confidence: 99%

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Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

et al. 2012

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Activation of the renin-angiotensin system (RAS) is thought to promote myocardial fibrosis. However, it is unclear whether this physiological fibrotic response results from chronic hemodynamic stress or from direct cellular signaling. Male C57B/6 mice were randomly assigned to receive angiotensin II (AngII) (2.0 lg kg À1 min À1 ), AngII+hydralazine (6.9 lg kg À1 min À1 ) or saline (control) via osmotic pumps for 7 days. Blood pressure was measured via noninvasive plethysmography. Hearts were harvested and processed for analysis. Cellular infiltration and collagen deposition were analyzed using histological staining. Molecular mediators were assessed using quantitative RT-PCR. As previously described, animals that received AngII developed hypertension and multifocal cellular infiltration by SMA + /CD133 + fibroblast progenitors followed by collagen deposition. The coadministration of hydralazine with AngII completely inhibited the hypertensive effects of AngII (Pp0.01) and resulted in minimal cellular infiltration and minimal collagen deposition. These findings were in the context of persistent RAS activation, which was evidenced by elevation in serum aldosterone levels in animals that received AngII or AngII+hydralazine compared with animals that received saline. At the molecular level, infusion of AngII resulted in the significant upregulation of profibrotic factors (connective tissue growth factor-7.8±0.7 fold), proinflammatory mediators (TNFa-4.6±0.8 fold; IL-1b-6.4±2.6 fold) and chemokines (CCL2-3.8 ± 1.0 fold; CXCL12-3.2 ± 0.4 fold), which were inhibited when hydralazine was also infused. We provide evidence that myocardial infiltration by fibroblast progenitor cells secondary to AngII and the resultant fibrosis can be prevented by the addition of hydralazine. Furthermore, the beneficial effects of hydralazine were observed while maintaining RAS activation, suggesting that the mechanism of fibrosis is blood pressure dependent.

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“…RAAS is considered to have a prime role in hypertensive cardiomyopathy even though several growth factors influence initiation and maintenance of myocardial hypertrophy. Both angiotensin II and aldosterone are shown to contribute to myocardial fibrosis (Sopel et al, 2011;Struthers & Unger, 2011). Correlation between circulating renin-angiotensin levels and left ventricular mass have long been established and same has been proved by the study showing regression of hypertensive left ventricular hypertrophy upon targeting RAAS (Solomon et al, 2009).…”

Section: Up Regulated Renin-angiotensin-aldosterone and Sympathetic Smentioning

confidence: 91%

The Evolving Face of Heart Failure Associated with Elevated Cardio-Metabolic Risk Factors

Dutt¹,

Chauthaiwale²,

Mohanan³

et al. 2012

Cardiomyopathies - From Basic Research to Clinical Management

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Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

Cited by 65 publications

References 41 publications

Effects of apelin on the cardiovascular system

Effects of apelin on the cardiovascular system

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

The Evolving Face of Heart Failure Associated with Elevated Cardio-Metabolic Risk Factors

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