The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

Zhang, Shaosong; Weinheimer, Carla J.; Courtois, Michael; Kovács, Attila; Zhang, Cindy E.; Cheng, Alec M.; Wang, Yibin; Muslin, Anthony J.

doi:10.1172/jci200316290

Cited by 61 publications

(79 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to our findings, FAK-induced p38 activation has been observed in cardiac myocytes, where mechanical stretch phosphorylates FAK to generate a binding site for grb2, a scaffolding protein that links FAK to the MAPK pathway (45). In endothelial cells, Li et al (46) reported a transient activation of p38 after exposure to 12 dynes/cm 2 shear, but they did not measure the effect of lower intensities.…”

Section: Discussionsupporting

confidence: 87%

Low Intensity Shear Stress Increases Endothelial ELR+ CXC Chemokine Production via a Focal Adhesion Kinase-p38β MAPK-NF-κB Pathway

Shaik

Soltau

Chaturvedi

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

CXC chemokines with a glutamate-leucine-arginine (ELR) tripeptide motif (ELR؉ CXC chemokines) play an important role in leukocyte trafficking into the tissues. For reasons that are not well elucidated, circulating leukocytes are recruited into the tissues mainly in small vessels such as capillaries and venules. Because ELR ؉ CXC chemokines are important mediators of endothelial-leukocyte interaction, we compared chemokine expression by microvascular and aortic endothelium to investigate whether differences in chemokine expression by various endothelial types could, at least partially, explain the microvascular localization of endothelial-leukocyte interaction. Both in vitro and in vivo models indicate that ELR ؉ CXC chemokine expression is higher in microvascular endothelium than in aortic endothelial cells. These differences can be explained on the basis of the preferential activation of endothelial chemokine production by low intensity shear stress. Low shear activated endothelial ELR ؉ CXC chemokine production via cell surface heparan sulfates, ␤ 3 -integrins, focal adhesion kinase, the mitogen-activated protein kinase p38␤, mitogen-and stress-associated protein kinase-1, and the transcription factor.

show abstract

Section: Discussionsupporting

confidence: 87%

Low Intensity Shear Stress Increases Endothelial ELR+ CXC Chemokine Production via a Focal Adhesion Kinase-p38β MAPK-NF-κB Pathway

Shaik

Soltau

Chaturvedi

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…23 Recent work by our group showed that Grb2 function is required for pressure overload-induced cardiac hypertrophy. 24 In contrast, we and others showed that p38␣ and p38␤ MAPK are not required for hypertrophy and, surprisingly, may have an antihypertrophic function in vivo. 24,25 The role of Raf/MEK/ERK signaling in the pathogenesis of cardiac hypertrophy is controversial.…”

mentioning

confidence: 61%

Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

et al. 2004

Self Cite

View full text Add to dashboard Cite

Background-Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality.Mechanical stress in the heart results in the activation of the small GTPase ras and the Raf-1/MEK/ERK signaling cascade in addition to other signaling pathways. Methods and Results-In an attempt to determine the requirement for the serine/threonine kinase Raf-1 in the pathogenesis of cardiac hypertrophy, we generated transgenic mice with cardiac-specific expression of a dominant negative form of Raf-1 (DN-Raf). DN-Raf mice appeared normal at birth, were fertile, and had normal cardiac structure and function in the absence of provocative stimulation. In response to pressure overload, cardiac extracellular signal-regulated kinase (ERK) activation was inhibited, but c-Jun N-terminal kinase (JNK) activation and p38 mitogen-activated protein kinase (MAPK) activation were normal. DN-Raf mice were sensitized to pressure overload and the development of cardiomyocyte apoptosis, and Ͼ35% of animals died within 7 days of aortic banding. Surviving DN-Raf animals were markedly resistant to the development of cardiac hypertrophy and hypertrophic gene induction in response to transverse aortic constriction. Conclusions-These results establish that Raf-1 kinase activity is essential for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload.

show abstract

“…12 Sham-operated animals underwent surgery but without aortic constriction. Seven days after surgery, echocardiographic images were acquired and analyzed using described methods.…”

Section: Induction Of Lvhmentioning

confidence: 99%

“…Seven days after surgery, echocardiographic images were acquired and analyzed using described methods. 12,13 …”

Section: Induction Of Lvhmentioning

confidence: 99%

Left Ventricular Hypertrophy

Ebert¹

2005

Easy ECG

View full text Add to dashboard Cite

Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.

show abstract

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

Cited by 61 publications

References 33 publications

Low Intensity Shear Stress Increases Endothelial ELR+ CXC Chemokine Production via a Focal Adhesion Kinase-p38β MAPK-NF-κB Pathway

Low Intensity Shear Stress Increases Endothelial ELR+ CXC Chemokine Production via a Focal Adhesion Kinase-p38β MAPK-NF-κB Pathway

Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

Left Ventricular Hypertrophy

Contact Info

Product

Resources

About