Signal transduction in cardiac hypertrophy — dissecting compensatory versus pathological pathways utilizing a transgenic approach

doi:10.1016/S1471-4892(01)00029-7

Current Opinion in Pharmacology

Volume 1, Issue 2, 1 April 2001, Pages 134-140

https://doi.org/10.1016/S1471-4892(01)00029-7 Get rights and content

Abstract

Targeted and regulated genetic manipulation, physiological intervention to introduce biomechanical stress and injury, sophisticated measurement of cardiac function in transgenic heart at whole organ and cellular level, and the molecular/biochemical/genomic analysis of signaling pathways in cardiomyocytes represent the most significant advances in recent years in this field. Such progress has helped make inroads into understanding the molecular mechanism of cardiac hypertrophy and heart failure. Delineating intracellular signaling pathways involved in the different aspects of cardiac hypertrophy and remodeling will have significant implications in drug development for heart failure.

Introduction

Two basic mechanisms are implicated in the heart to cope with increased hemodynamic burden. One works in the short term to transiently enhance cardiac contractility, for example, through elevated stimulation of β-adrenergic signaling pathway. The long-term response involves a remodeling process characterized by enlargement of muscle cells, termed cardiac hypertrophy [1]. At early stages cardiac hypertrophy results in the thickening of the myocardial wall, improved cardiac contraction and reduced myocardial stress, thus it is viewed as a compensatory process. Under prolonged pathological stress, however, cardiac hypertrophy is accompanied by interstitial fibrosis, contractile dysfunction, altered gene expression pattern, changes in energy metabolism and abnormal electrophysiological properties, which eventually lead to overt decompensated heart failure [2]. Such observation leads to the assumption that although cardiac hypertrophy in itself is a compensatory event, it is also part of the pathological process that triggers the onset of heart failure. Questions remain, however, whether compensatory cardiac hypertrophy and the associated pathological remodeling are mediated by a common signaling pathway, or related events mediated by distinct pathways; therefore, understanding the cellular mechanism of cardiac hypertrophy in order to distinguish the molecular basis of compensatory versus pathological process should hold great promise in finding an effective treatment for heart failure.

The recent advancement in molecular genetics, combined with single cell and whole organ physiology, allows studies of individual signaling pathways involved in cardiac hypertrophy at an unprecedented depth and pace 3., 4.. A large number of genetically engineered animal models have now been generated that permit the molecular dissection of distinct pathways and their potential cross-talk in an in vivo context 3., 5., 6., 7., 8., 9.. From these studies, a number of signaling pathways are implicated that play important roles in the process of cardiac hypertrophy and heart failure, including gp130/Stat, small G proteins, G_q/protein kinase C (PKC), mitogen-activated protein (MAP) kinase, calcium/calmodulin dependent protein kinase (CaMK) and calcineurin 9., 10., 11., 12., 13., 14., 15.. The main purpose of this review is to highlight some of the most significant progress from transgenic studies, focusing on the new insights into the specific effects and cross-talk among these pathways. This exciting new development will certainly help to identify novel strategies to develop drug-based and gene-based therapy for heart failure.

Section snippets

Tyrosine kinase receptor gp130 signaling in cardiac hypertrophy and survival

Using a high-throughput cardiac myocyte hypertrophy assay system, a hypertrophic molecule, cardiotrophin-1 (CT-1), was discovered as a new member of the interleukin-6 (IL-6) cytokine family [16]. It functions through the gp130/leukemia inhibitory factor (LIF) heterodimeric receptor, a member of the tyrosine kinase receptor family [10]. Activation of the gp130 pathway by cardiotrophin-1 in neonatal cardiomyocytes induces characteristic features of hypertrophy and promotes survival by inhibiting

Small G proteins in cardiac hypertrophy and contractile dysfunction

Three members of the small GTP-binding protein family, Ras, Rac1 and RhoA, have been previously implicated in cardiac hypertrophy in neonatal cardiac myocytes [11]. Activation of Ras (v12Ras), Rac (v12Rac1) and RhoA (v14Rho) activities induce atrial natriuretic factor (ANF) expression and, in some cases, promote myofilament organization 24., 25., 26., 27., 28., 29., whereas the expression of dominant negative mutants of Ras, Rac and RhoA inhibits or attenuates the effects of hypertrophic

Angiotensin II, G_q and Protein kinase C in hypertrophy

In cardiac tissue, angiotensin II (Ang II) interacts with both type 1 (AT₁) and type 2 (AT₂) receptors but the relative levels of receptor protein shifts from predominantly AT₁ in normal heart to predominantly AT₂ in diseased heart while overall content is downregulated [36]. Earlier studies suggest that AT₁ is the mediator of chronotrophic and hypertrophic effects of angiotensin II whereas AT₂ receptor activation causes functional antagonism of AT₁-mediated effects. Studies in cultured

MAP kinases in compensatory hypertrophy and cardiomyopathy

The MAP kinase family has three major subfamilies: extracellular signal regulated kinase (ERK), c-Jun N-terminus kinase (JNK) and p38 kinase. Each consists of cascades of MEKKs (MAP kinase kinase kinases), MKKs (dual specific MAP kinase kinases) and MAP kinases [48]. Although MAP kinase activation has been correlated with the onset of cardiac hypertrophy and heart failure, its specific role in the intact heart is still not yet fully established. ERK is shown to be an essential component of

Calcium-induced transcriptional mechanism of hypertrophy

Recent studies have implicated two transcriptional pathways in calcium-mediated signaling during hypertrophy. One is calcineurin-mediated activation of NFAT3 (nuclear factor of activated T-cell 3) and GATA-4 (GATA motif binding protein-4) and the other is CaMK mediated activation of MEF-2 (myocyte enhancer factor-2) 55., 56. The calcineurin pathway, and the controversies surrounding the effect of calcineurin inhibitor on mechanical stress induced hypertrophy or other genetic models of

Conclusions: genetic dissection of cardiac hypertrophy and heart failure, a perspective for future studies

In conclusion, combining genetic perturbation with biomechanical manipulation in experimental animals has helped us to identify pathways that are involved in the compensatory response versus those that are involved in pathological hypertrophy and remodeling (Fig. 1). Despite tremendous progress, current transgenic techniques still need to be improved to distinguish developmental factors and nonspecific effects from physiologically relevant functions. Approaches with more precise control of

Acknowledgements

This work is supported by grant HL62311 from the National Institutes of Health and a Grant-in-Aid from the American Heart Association, Mid-Atlantic Affiliate to YW. The author apologizes to investigators whose studies were not included in this article due to limited space and thanks B Petrich for his assistance in the preparation of the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

of special interest
of outstanding interest

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The GqPCR-PLC-PIP2 signaling pathway is arguably the most important cell signaling pathway involved in cardiac hypertrophy and failure (8). It is well established that activation of Gq/PLC signaling via several extracellular signals directly stimulates the hypertrophic response, and blocking the Gq/PLC pathway in vivo can partially attenuate the hypertrophy induced by pressure overload (16). Some important hypertrophic agonists, including norepinephrine (NE) and angiotensin II (Ang II), are well established GqPCR agonists (17); their involvement in the development of different types of cardiac hypertrophy has been well documented (8, 16, 18, 19).
The seemly paradoxical G_q agonist-stimulated phosphoinositide production has long been known, but the underlying mechanism and its physiological significance are not known. In this study, we studied cardiac phosphoinositide levels in both cells and whole animals under the stimulation of norepinephrine (NE), angiotensin II (Ang II), and other physiologically relevant interventions. The results demonstrated that activation of membrane receptors related to NE or Ang II caused an initial increase and a later fall in phosphatidylinositol 4,5-bisphosphate (PIP₂) levels in the primary cultured cardiomyocytes from adult rats. The possible mechanism underlying this increase in PIP₂ was found to be through an enhanced activity of phosphatidylinositol 4-kinase IIIβ, which was mediated by an up-regulated interaction between phosphatidylinositol 4-kinase IIIβ and PKC; the increased activity of phosphatidylinositol 4-phosphate 5-kinase γ was also involved for NE-induced increase of PIP₂. When the systolic functions of the NE/Ang II-treated cells were measured, a maintained or failed contractility was found to be correlated with a rise or fall in corresponding PIP₂ levels. In two animal models of cardiac hypertrophy, PIP₂ levels were significantly reduced in hypertrophic hearts induced by isoprenaline but not in those induced by swimming exercise. This study describes a novel mechanism for phosphoinositide metabolism and modulation of cardiac function.
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The effect of cystamine treatment on levels of p-MEK5 and p-ERK5 in LV tissues of Balb/c mice was insignificant (p > 0.12). It is recognized that JNKs and p38 MAPK are critical for inducing hypertrophic responses via up-regulating specific gene expression and the consequent protein synthesis (Wang, 2001). Involvement of JNK and p38 MAPK upon cystamine treatment in SLE setting was elucidated with focuses on phosphorylation of JNK and p38 MAPK and the expression level of c-Jun.
The aim of this study is to investigate the protective effects of cystamine on lupus-associated cardiac hypertrophy.
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Cystamine decreased both left ventricular (LV) mass and LV mass/tissue-to-blood ratio (TBR) in NZB/W-F1 mice (p < 0.05), whereas slight effects were observed in Balb/c mice. Moreover, cystamine reduced levels of atrial natriuretic peptide (ANP), C-reactive protein (CRP), heart type-fatty acid binding protein (h-FABP), creatine kinase-MB (CK-MB) and IL-6 in LV tissues of NZB/W-F1 mice (p < 0.05). Additionally, in LV tissues of NZB/W-F1 mice, suppression of hypertrophic signaling mediated by IL-6 in response to administration of cystamine was revealed, including phosphorylation of MEK5, ERK5, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) (p < 0.05).
Cystamine alleviated LV hypertrophy in NZB/W-F1 mice as a result of decrease in hypertrophic mediators and suppression of IL-6 mediated hypertrophic signaling.
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Madecassoside (MA) is a major triterpenoid component of Centella asiatica that has a wide range of biological activities, including wound-healing and antioxidative activities. In the present study, we evaluated the therapeutic effect of MA on rat cardiac dysfunction during sepsis induced by lipopolysaccharide (LPS), as well as the possible mechanism. Pretreatment of the neonatal rat cardiomyocytes with MA inhibited LPS-induced TNF-α production in a concentration-dependent manner. In addition, pretreatment of the rats with MA (20 mg/kg, i.g.) significantly inhibited the elevation of plasma TNF-α, delayed the fall of mean arterial blood pressure, and attenuated the tachycardia induced by LPS. We further observed that MA prevented the LPS-induced nuclear factor-kappa B (NF-κB) translocation from the cytoplasm into the nucleus, and inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38. These results suggest that MA inhibits LPS-stimulated TNF-α production through the blocking of ERK1/2, p38 and NF-κB pathways in cardiomyocytes. MA may have cardioprotective effects in LPS-mediated sepsis.
Molecular targets and regulators of cardiac hypertrophy
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Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli. It enables myocytes to increase their work output, which improves cardiac pump function. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world. A number of signaling modulators that influence gene expression, apoptosis, cytokine release and growth factor signaling, etc. are known to regulate heart. By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed. This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy. In this review, we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin, cGMP, NFAT, natriuretic peptides, histone deacetylase, IL-6 cytokine family, Gq/G11 signaling, PI3K, MAPK pathways, Na/H exchanger, RAS, polypeptide growth factors, ANP, NO, TNF-α, PPAR and JAK/STAT pathway, microRNA, Cardiac angiogenesis and gene mutations in adult heart. Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy. The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy, with special emphasis on novel researches and investigations.
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Citation Excerpt :
Additional studies utilizing siRNA to the variant-specific C-terminal domain will be required to define the contribution of each individual splice variant. There is growing evidence that p38 and/or JNK activation may be implicated in cardiac hypertrophy, congestive heart failure, and ischemia/reperfusion injury (27-33). Previous studies of transgenic animals with cardiac-restricted overexpression of MLK7 demonstrated increased β-adrenergic stimulated p38 and JNK activation relative to littermate controls that is associated with negative effects on contractility (22), suggesting MLK7 to be a MAPKKK involved in negative inotropic effects of stress pathway activation in this tissue.
Mixed lineage kinase 7 (MLK7) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the pro-apoptotic signaling pathways p38 and JNK. A library of potential kinase inhibitors was screened, and a series of dihydropyrrolopyrazole quinolines was identified as highly potent inhibitors of MLK7 in vitro catalytic activity. Of this series, an aryl-substituted dihydropyrrolopyrazole quinoline (DHP-2) demonstrated an IC₅₀ of 70 nm for inhibition of pJNK formation in COS-7 cell MLK7/JNK co-transfection assays. In stimulated cells, DHP-2 at 200 nm or MLK7 small interfering RNA completely blocked anisomycin and UV induced but had no effect on interleukin-1β or tumor necrosis factor-α-induced p38 and JNK activation. Additionally, the compound blocked anisomycin and UV-induced apoptosis in COS-7 cells. Heart tissue homogenates from MLK7 transgenic mice treated with DHP-2 at 30 mg/kg had reduced JNK and p38 activation with no apparent effect on ERK activation, demonstrating that this compound can be used to block MLK7-driven MAPK pathway activation in vivo. Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo.

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ReviewSignal transduction in cardiac hypertrophy — dissecting compensatory versus pathological pathways utilizing a transgenic approach

Abstract

Introduction

Section snippets

Tyrosine kinase receptor gp130 signaling in cardiac hypertrophy and survival

Small G proteins in cardiac hypertrophy and contractile dysfunction

Angiotensin II, Gq and Protein kinase C in hypertrophy

MAP kinases in compensatory hypertrophy and cardiomyopathy

Calcium-induced transcriptional mechanism of hypertrophy

Conclusions: genetic dissection of cardiac hypertrophy and heart failure, a perspective for future studies

Acknowledgements

References and recommended reading

J Card Fail

J Nucl Cardiol

Curr Opin Genet Dev

Trends Cardiovasc Med

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Mol Cell Cardiol

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Cell

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Semin Immunol

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Cell Signal

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Signal transduction during cardiac hypertrophy: the role of G alpha q, PLC beta I, and PKC [editorial]

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Review
Signal transduction in cardiac hypertrophy — dissecting compensatory versus pathological pathways utilizing a transgenic approach

Angiotensin II, G_q and Protein kinase C in hypertrophy