ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy

Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context.

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Omentin-1 attenuates glucocorticoid-induced cardiac injury by phosphorylating GSK3β

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0236 ◽

2021 ◽

Vol 66 (4) ◽

pp. 273-283

Author(s):

Zhousheng Jin ◽

Fangfang Xia ◽

Jiaojiao Dong ◽

Tingting Lin ◽

Yaoyao Cai ◽

...

Keyword(s):

Side Effects ◽

Cardiac Hypertrophy ◽

Cardiac Injury ◽

Experimental Studies ◽

Chronic Administration ◽

Cardiovascular Complications ◽

Rat Serum ◽

Cardiac Side Effects ◽

Beneficial Effects

Glucocorticoid excess often causes a variety of cardiovascular complications, including hypertension, atherosclerosis, and cardiac hypertrophy. To abrogate its cardiac side effects, it is necessary to fully disclose the pathophysiological role of glucocorticoid in cardiac remodelling. Previous clinical and experimental studies have found that omentin-1, one of the adipokines, has beneficial effects in cardiovascular diseases, and is closely associated with metabolic disorders. However, there is no evidence to address the potential role of omentin-1 in glucocorticoid excess-induced cardiac injuries. To uncover the links, the present study utilized rat model with glucocorticoid-induced cardiac injuries and clinical patients with abnormal cardiac function. Chronic administration of glucocorticoid excess reduced rat serum omentin-1 concentration, which closely correlated with cardiac functional parameters. Intravenous administration of adeno-associated virus encoding omentin-1 upregulated the circulating omentin-1 level and attenuated glucocorticoid excess-induced cardiac hypertrophy and functional disorders. Overexpression of omentin-1 also improved cardiac mitochondrial function, including the reduction of lipid deposits, induction of mitochondrial biogenesis, and enhanced mitochondrial activities. Mechanistically, omentin-1 phosphorylated and activated the GSK3β pathway in the heart. From a study of 28 patients with Cushing’s syndrome and 23 healthy subjects, the plasma level of glucocorticoid was negatively correlated with omentin-1, and was positively associated with cardiac ejection fraction and fractional shortening. Collectively, the present study provided a novel role of omentin-1 in glucocorticoid excess-induced cardiac injuries and found that the omentin-1/GSK3β pathway was a potential therapeutic target in combating the side effects of glucocorticoid.

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Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽

10.1055/a-1191-7970 ◽

2020 ◽

Vol 86 (17) ◽

pp. 1304-1312

Author(s):

Nurmila Sari ◽

Yasufumi Katanasaka ◽

Hiroki Honda ◽

Yusuke Miyazaki ◽

Yoichi Sunagawa ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Gene Transcription ◽

Binding Protein ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

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Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

Scientific Reports ◽

10.1038/s41598-020-75128-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ning Zhou ◽

Xin Chen ◽

Jing Xi ◽

Ben Ma ◽

Christiana Leimena ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Pressure Overload ◽

Bioinformatic Analysis ◽

Pathological Cardiac Hypertrophy ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Survival Signaling ◽

G Protein Coupled

Abstract Pressure overload-induced cardiac hypertrophy, such as that caused by hypertension, is a key risk factor for heart failure. However, the underlying molecular mechanisms remain largely unknown. We previously reported that the valosin-containing protein (VCP), an ATPase-associated protein newly identified in the heart, acts as a significant mediator of cardiac protection against pressure overload-induced pathological cardiac hypertrophy. Still, the underlying molecular basis for the protection is unclear. This study used a cardiac-specific VCP transgenic mouse model to understand the transcriptomic alterations induced by VCP under the cardiac stress caused by pressure overload. Using RNA sequencing and comprehensive bioinformatic analysis, we found that overexpression of the VCP in the heart was able to normalize the pressure overload-stimulated hypertrophic signals by activating G protein-coupled receptors, particularly, the olfactory receptor family, and inhibiting the transcription factor controlling cell proliferation and differentiation. Moreover, VCP overexpression restored pro-survival signaling through regulating alternative splicing alterations of mitochondrial genes. Together, our study revealed a novel molecular regulation mediated by VCP under pressure overload that may bring new insight into the mechanisms involved in protecting against hypertensive heart failure.

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Abstract 63: Reduction in Glucocorticoid Receptor Expression Attenuates Pressure Overload-induced Cardiac Hypertrophy and Promotes Heart Failure in Mice

Circulation Research ◽

10.1161/res.119.suppl_1.63 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Rongxue Wu ◽

Maura Knapp ◽

Mei Zheng ◽

James K Liao

Keyword(s):

Heart Failure ◽

Glucocorticoid Receptor ◽

Cardiac Hypertrophy ◽

Imaging System ◽

Pressure Overload ◽

Left Ventricular ◽

Receptor Expression ◽

Heart Weight ◽

Homozygous Mutation ◽

Compensatory Mechanism

Background: Left ventricular hypertrophy (LVH) is an independent risk factor for heart failure and sudden death. In addition, LVH is also a compensatory mechanism that helps the heart cope with pressure overload. Stress is considered one factor that is related to cardiac outcomes. Glucocorticoids are primary stress hormones, whose role in the heart is poorly understood. Here, we hypothesize that a reduction in the expression of the glucocorticoid receptor (GR) would decrease cardiac hypertrophy in response to pressure overload. Methods and Results: The GR homozygous mutation (GR-/-) is embryonic lethal. However, GR heterozygous mice (GR+/-) show a normal phenotype. We subjected GR+/- mice to transverse aortic constriction (TAC). At four weeks after TAC, the ratio of heart weight to tibia length increased significantly in wild-type mice (control) littermates compared with GR+/- mice. Cardiac myocyte size was also smaller in GR+/- mice vs controls, suggesting an attenuated cardiac growth response in these mice. In addition, GR+/- hearts displayed increased cell death and enhanced fibrosis in response to TAC. Cardiac function, determined by EF% and FS% (measured using the Vevo2100 imaging system), was significantly reduced in GR+/- mice compared with controls at eight weeks post-operation, while LVEDD was increased. Together, with the increased ratio of lung weight to body weight in GR+/- mice at eight weeks following TAC, this suggests an exaggerated heart failure in GR+/- mice. In vitro, hydrocortisone-induced cell growth in H9c2 cells was abolished by GR knockdown using siRNA. Finally, we looked at the mechanisms by which GR may play a role in the development of hypertrophy. We found reduced ERK-JNK activity in GR+/- hearts, suggesting that the reduced hypertrophic response in GR+/- mice occurs, at least partially, through abolished JNK and ERK activity. Conclusion: The glucocorticoid receptor is required for cardiac hypertrophy and protects the heart from heart failure during cardiac pressure overload.

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Phosphorylation of JAK2 at Serine 523: a Negative Regulator of JAK2 That Is Stimulated by GrowthHormone and Epidermal Growth Factor

Molecular and Cellular Biology ◽

10.1128/mcb.01591-05 ◽

2006 ◽

Vol 26 (11) ◽

pp. 4052-4062 ◽

Cited By ~ 39

Author(s):

Anna M. Mazurkiewicz-Munoz ◽

Lawrence S. Argetsinger ◽

Jean-Louis K. Kouadio ◽

Allan Stensballe ◽

Ole N. Jensen ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Tyrosine Kinases ◽

Kinase Activity ◽

Negative Regulator ◽

Affinity Enrichment ◽

Extracellular Signal ◽

Epidermal Growth ◽

A Site ◽

G Protein Coupled

ABSTRACT The tyrosine kinase JAK2 is a key signaling protein for at least 20 receptors in the cytokine/hematopoietin receptor superfamily and is a component of signaling for multiple receptor tyrosine kinases and several G-protein-coupled receptors. In this study, phosphopeptide affinity enrichment and mass spectrometry identified serine 523 (Ser523) in JAK2 as a site of phosphorylation. A phosphoserine 523 antibody revealed that Ser523 is rapidly but transiently phosphorylated in response to growth hormone (GH). MEK1 inhibitor UO126 suppresses GH-dependent phosphorylation of Ser523, suggesting that extracellular signal-regulated kinases (ERKs) 1 and/or 2 or another kinase downstream of MEK1 phosphorylate Ser523 in response to GH. Other ERK activators, phorbol 12-myristate 13-acetate and epidermal growth factor, also stimulate phosphorylation of Ser523. When Ser523 in JAK2 was mutated, JAK2 kinase activity as well as GH-dependent tyrosyl phosphorylation of JAK2 and Stat5 was enhanced, suggesting that phosphorylation of Ser523 inhibits JAK2 kinase activity. We hypothesize that phosphorylation of Ser523 in JAK2 by ERKs 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner to dampen activation of JAK2 in response to GH and provides a mechanism by which prior exposure to environmental factors that regulate Ser523 phosphorylation might modulate the cell's response to GH.

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Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Biochemical Journal ◽

10.1042/bj3300489 ◽

1998 ◽

Vol 330 (1) ◽

pp. 489-495 ◽

Cited By ~ 37

Author(s):

N. Maria GARNOVSKAYA ◽

Yurii MUKHIN ◽

R. John RAYMOND

Keyword(s):

Protein Kinase ◽

G Protein ◽

Tyrosine Kinases ◽

Proton Exchange ◽

Response Curves ◽

Extracellular Signal ◽

Sodium Proton Exchange ◽

Time Courses ◽

Rapid Activation ◽

G Protein Coupled

These experiments tested the hypothesis that signalling elements involved in the activation of the extracellular signal-regulated protein kinase (ERK) mediate rapid activation of sodium-proton exchange (NHE) in fibroblasts when both signals are initiated by a single G protein-coupled receptor, the 5-HT1A receptor. Similarities between the two processes were comparable concentration-response curves and time-courses, and overlapping sensitivity to some pharmacological inhibitors of tyrosine kinases (staurosporine and genistein), and phosphoinositide 3ʹ-kinase (wortmannin and LY204002). Activation of NHE was much more sensitive to the phosphatidylcholine-specific phospholipase inhibitor (D609) than was ERK. Neither pathway was sensitive to manoeuvres designed to block PKC. In contrast, Src or related kinases appear to be required to activate ERK, but not NHE. Transfection of cDNA constructs encoding inactive mutant phosphoinositide 3ʹ-kinase, Grb2, Sos, Ras, and Raf molecules were successful in attenuating ERK, but had essentially no effect upon NHE activation. Finally, PD98059, an inhibitor of mitogen activated/extracellular signal regulated kinase kinase, blocked ERK but not NHE activation. Thus, in CHO fibroblast cells, activation by the 5-HT1A receptor of ERK and NHE share a number of overlapping features. However, our studies do not support a major role for ERK, when activated by the 5-HT1A receptor, as a short-term upstream regulator of NHE activity.

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Cooperative Binding of ETS2 and NFAT Link Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy

Circulation ◽

10.1161/circulationaha.120.052384 ◽

2021 ◽

Author(s):

Yuxuan Luo ◽

Nan Jiang ◽

Herman I. May ◽

Xiang Luo ◽

Anwarul Ferdous ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Target Genes ◽

Critical Role ◽

Pressure Overload ◽

Marker Genes ◽

Activated T Cells ◽

Hypertrophic Growth ◽

Conditional Deletion ◽

Extracellular Signal

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. Methods: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. Conclusions: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.

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Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons

Science ◽

10.1126/science.aaw5937 ◽

2019 ◽

Vol 365 (6456) ◽

pp. 929-934 ◽

Cited By ~ 23

Author(s):

Ruobo Zhou ◽

Boran Han ◽

Chenglong Xia ◽

Xiaowei Zhuang

Keyword(s):

Tyrosine Kinases ◽

Super Resolution ◽

Erk Signaling ◽

Extracellular Signal Regulated Kinase ◽

Rtk Signaling ◽

Extracellular Signal ◽

Extracellular Stimuli ◽

Resolution Imaging ◽

G Protein Coupled

Actin, spectrin, and related molecules form a membrane-associated periodic skeleton (MPS) in neurons. The function of the MPS, however, remains poorly understood. Using super-resolution imaging, we observed that G protein–coupled receptors (GPCRs), cell adhesion molecules (CAMs), receptor tyrosine kinases (RTKs), and related signaling molecules were recruited to the MPS in response to extracellular stimuli, resulting in colocalization of these molecules and RTK transactivation by GPCRs and CAMs, giving rise to extracellular signal–regulated kinase (ERK) signaling. Disruption of the MPS prevented such molecular colocalizations and downstream ERK signaling. ERK signaling in turn caused calpain-dependent MPS degradation, providing a negative feedback that modulates signaling strength. These results reveal an important functional role of the MPS and establish it as a dynamically regulated platform for GPCR- and CAM-mediated RTK signaling.

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Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00759.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. H2190-H2197 ◽

Cited By ~ 39

Author(s):

Hideyuki Takaoka ◽

Giovanni Esposito ◽

Lan Mao ◽

Hiroyuki Suga ◽

Howard A. Rockman

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Wall Stress ◽

Left Ventricular ◽

Lv Function ◽

Compensatory Mechanism ◽

Compensatory Response ◽

Myocardial Stiffness ◽

Stiffness Constant

Pressure overload cardiac hypertrophy may be a compensatory mechanism to normalize systolic wall stress and preserve left ventricular (LV) function. To test this concept, we developed a novel in vivo method to measure myocardial stress (ς)-strain (ɛ) relations in normal and hypertrophied mice. LV volume was measured using two pairs of miniature omnidirectional piezoelectric crystals implanted orthogonally in the endocardium and one crystal placed on the anterior free wall to measure instantaneous wall thickness. Highly linear ς-ε relations were obtained in control ( n = 7) and hypertrophied mice produced by 7 days of transverse aortic constriction (TAC; n = 13). Administration of dobutamine in control mice significantly increased the load-independent measure of LV contractility, systolic myocardial stiffness. In TAC mice, systolic myocardial stiffness was significantly greater than in control mice (3,156 ± 1,433 vs. 1,435 ± 467 g/cm2, P < 0.01), indicating enhanced myocardial contractility with pressure overload. However, despite the increased systolic performance, both active (time constant of LV pressure decay) and passive (diastolic myocardial stiffness constant) diastolic properties were markedly abnormal in TAC mice compared with control mice. These data suggest that the development of cardiac hypertrophy is associated with a heightened contractile state, perhaps as an early compensatory response to pressure overload.

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