c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II–Induced Hypertension

Callera, Gláucia E.; Antunes, Tayze T.; He, Ying; Montezano, Augusto C.; Yogi, Álvaro; Savoia, Carmine; Touyz, Rhian M.

doi:10.1161/hypertensionaha.116.07699

Cited by 28 publications

(22 citation statements)

References 51 publications

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“…Three new AT 1 R residues were found to form critical interactions, Tyr 35 , Trp 84 and Arg 167 , in which Arg 167 may be essential in determining ligand binding and selectivity. The study further supports the notion that AT 1 R has a sodium binding pocket, and Asn 111 and Asn 295 in transmembrane domain III and VII, respectively, facilitate receptor activation (1245,1246). In addition, AT 1 R activation by ANG II promotes a conformational change in the TM3-TM6 region causing an interaction between TM2 and TM7 (703).…”

Section: Structure Internalization and Expressionsupporting

confidence: 82%

“…Although c-Src is implicated in both ANG II-induced NADPH oxidase activity (1062) and EGFR transactivation (819), its exact role in ANG II-induced cardiac fibrosis is unclear. c-Src deficiency or pharmacological inhibition was found to attenuate ANG II-induced hypertension, cardiac hypertrophy, and oxidative stress, as well as improve cardiac and endothelial function; however, both vascular and cardiac fibrosis are enhanced (111). While not fully explained, these findings do provide further support to the conclusion that ANG II causes cardiac fibrosis independent of increased blood pressure.…”

Section: Src Transcriptional Factors and Mapk Familymentioning

confidence: 83%

“…A Src family kinase inhibitor prevents ANG II-induced MLC phosphorylation and vascular contraction (847). Moreover, ANG II-dependent hypertension, but not vascular remodeling, is attenuated in c-Srcϩ/Ϫ mice (111). ANG II is known to activate IKK2/IKK-␤ leading to NF-B activation in VSMCs (1252), and inhibition of IKK2 attenuates the contractile response to ANG II.…”

Section: Tyrosine and Serine/threonine Kinases Involved In Vasoconstrmentioning

confidence: 99%

See 2 more Smart Citations

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

790

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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Section: Structure Internalization and Expressionsupporting

confidence: 82%

Section: Src Transcriptional Factors and Mapk Familymentioning

confidence: 83%

Section: Tyrosine and Serine/threonine Kinases Involved In Vasoconstrmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

790

780

View full text Add to dashboard Cite

show abstract

“…Src family kinases also regulate vascular contraction via MLCP, attenuating myosin light chain phosphorylation and contraction in AngII infused mice (30). AngII-dependent hypertension, but not vascular remodeling, is attenuated in c-Src+/− mice (31). Similarly, Ras-related protein 1 (Rap1b) knockdown or PDZ-RhoGEF/RhoA/Rho kinase signaling cascade promotes vascular contraction induced by AngII through inhibition of MLCP (32, 33).…”

Section: At1 Receptor Signaling In the Cardiovascular Systemmentioning

confidence: 99%

AT1 receptor signaling pathways in the cardiovascular system

Kawai

Forrester

O’Brien

et al. 2017

Pharmacological Research

175

126

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The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

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“…However, the detailed molecular mechanism by which pNaKtide reduces cardiac fibrosis remains to be further explored. Even though Src activation has been indicated to be related with increased tissue fibrosis, blocking Src activation with different methods has yield inconsistent results in reducing tissue fibrosis [134–136]. It will be interesting to test if pNaKtide exerts its effect on cardiac fibrosis solely through inhibition of Src, or if additional mechanisms are involved.…”

Section: Na/k-atpase As a Novel Target For Cardiac Fibrosismentioning

confidence: 99%

Reducing Cardiac Fibrosis: Na/K-ATPase Signaling Complex as a Novel Target

Fan

Xie

Tian

2017

Cardiovasc Pharm Open Access

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Cardiac fibrosis is a common pathological process in cardiac disease and may lead to heart failure. It can also cause sudden death even in those without cardiac symptoms. Tissue fibrosis can be categorized into two categories: replacement fibrosis (also called reparative fibrosis) and reactive fibrosis. In replacement fibrosis, infiltration of inflammatory cells and accumulation of Extracellular Matrix (ECM) proteins are the initial steps in forming scarlike fibrotic tissue after acute cardiac injury and cardiac cell necrosis. Reactive fibrosis can be formed in response to hormonal change and pressure or volume overload. Experimental studies in animals have identified important pathways such as the Renin-Angiotensin-Aldosterone System (RAAS) and the endothelin pathway that contribute to fibrosis formation. Despite the fact that clinical trials using RAAS inhibitors as therapies for reducing cardiac fibrosis and improving cardiac function have been promising, heart failure is still the leading cause of deaths in the United States. Intensive efforts have been made to find novel targets and to develop new treatments for cardiac fibrosis and heart failure in the past few decades. The Na/K-ATPase, a canonical ion transporter, has been shown to also function as a signal transducer and prolonged activation of Na/K-ATPase signaling has been found to promote the formation of cardiac fibrosis. Novel tools that block the activation of Na/K-ATPase signaling have been developed and have shown promise in reducing cardiac fibrosis. This review will discuss the recent development of novel molecular targets, focusing on the Na/K-ATPase signaling complex as a therapeutic target in treatment of cardiac fibrosis.

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c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II–Induced Hypertension

Cited by 28 publications

References 51 publications

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

AT1 receptor signaling pathways in the cardiovascular system

Reducing Cardiac Fibrosis: Na/K-ATPase Signaling Complex as a Novel Target

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