Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy

Tsybouleva, Natalia; Zhang, Lianfeng; Chen, Suetnee; Patel, Rajnikant; Lutucuta, Silvia; Nemoto, Shintaro; DeFreitas, Gilberto; Entman, Mark L.; Carabello, Blasé A.; Roberts, Robert; Marian, Ali J.

doi:10.1161/01.cir.0000121426.43044.2b

Cited by 217 publications

(194 citation statements)

References 54 publications

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“…Indeed, pressure-overloaded LIMP-2 KO mice show abnormal IDs on electron microscopy and their N-cadherin distribution is disturbed, suggesting a defect in the adherens junctions. The strength of adherens junctions is determined by the binding affi nity between N-cadherin and β-catenin (22), which is regulated by phosphorylation of the latter (19,20). We show in vivo as well as in vitro that loss of LIMP-2 disturbs this N-cadherin-β-catenin complex.…”

Section: Mechanisms Of Limp-2-mediated Response To Loadingmentioning

confidence: 84%

See 1 more Smart Citation

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Schroen¹,

Leenders²,

Erk³

et al. 2007

J Cell Biol

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Chronic cardiac loading as occurs during longstanding hypertension induces cardiac hypertrophy, which often progresses to left ventricle (LV) dysfunction and overt heart failure (HF). The molecular changes that precede and herald this transition from hypertrophy toward HF are incompletely understood (1).The intercalated disc (ID) of cardiac myocytes has emerged as a crucial structure in the heart. The cardiac ID consists of three major structures: gap junctions, adherens junctions, and desmosomes. In dilated cardiomyopathy, the number of gap junctions is decreased while the adherens junctions increase, leading to reduced cardiac communication and increased stiff ness (2). An important role for ID structure is further demonstrated by the fact that complete loss of ID proteins like N-cadherin, plakoglobin, and β-catenin (3-6) is lethal. Moreover, mutations in ID proteins like desmoplakin, desmoglobin, plakoglobin, and plakophilin-2 (7-9) cause human cardiomyopathies. However, factors that more subtly modulate the ID have not yet been described.We have previously reported on the unique propensity of the homozygous hypertensive transgenic rat TGR(mRen-2) 27 (Ren-2). A proportion of these rats rapidly progresses toward HF, The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also fi nd LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated -catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect.Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.Abbreviations used: ANF, atrial natriuretic factor; Ang, angiotensin; aska, α-skeletal actin; BNP, brain natriuretic peptide; HF, heart failure; ID, intercalated disc; IP, immunoprecipitation; LIMP-2, lysosomal integral membrane protein 2; LV, left ventricle; RCM, rat ventricular cardiac myocyte; shLIMP-2, short-hairpin RNA against LIMP-2; shRNA, short-hairpin RNA; TSP, thrombospondin.The online version of this article contains supplemental material.

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Section: Mechanisms Of Limp-2-mediated Response To Loadingmentioning

confidence: 84%

“…The functional integrity of the ID depends on the proper interaction between P(Ser37)-β-catenin and cadherin (19,20). Therefore, we investigated whether the absence of LIMP-2 aff ected the binding of P-β-catenin to cadherin.…”

Section: Limp-2 Regulates Id Integritymentioning

confidence: 99%

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Schroen¹,

Leenders²,

Erk³

et al. 2007

J Cell Biol

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“…PKD is activated by PMA and PE in a Bis I-sensitive manner in NRVMs (16). Aldosterone also activates PKD in cardiomyocytes in culture and in mice (46). Furthermore, Gö6976 inhibits fetal gene expression in cardiomyocytes activated by aldosterone.…”

Section: Discussionmentioning

confidence: 97%

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Vega

Harrison²,

Meadows

et al. 2004

Molecular and Cellular Biology

481

514

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A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation-and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.Coordinated changes in gene transcription during cell growth and differentiation require mechanisms for coupling intracellular signaling pathways with the genome. The acetylation of nucleosomal histones has emerged as a central mechanism in the control of gene transcription during such cellular transitions (20). Acetylation of histones by histone acetyltransferases promotes transcription by relaxing chromatin structure, whereas histone deacetylation by histone deacetylases (HDACs) reverses this process, resulting in transcriptional repression. How these chromatin-modifying enzymes are linked to, and controlled by, intracellular signaling is only beginning to be understood.There are two classes of HDACs that can be distinguished by their structures and expression patterns. Class I HDACs (HDAC1, HDAC2, and HDAC3) are expressed ubiquitously and are composed mainly of a catalytic domain (13). In contrast, class II HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) display more restricted expression patterns and contain an N-terminal extension, which mediates interactions with other transcriptional cofactors and confers responsiveness to calcium-dependent signaling (12,25,33). Signaling by calcium/ calmodulin-dependent protein kinase (CaMK) results in phosphorylation of the N termini of class II HDACs, which govern their intracellular localization and interactions with other factors (29, 32). Phosphorylation of signal-responsive serine residues creates docking sites for the 14-3-3 family of chaperone proteins, which promote shuttling of HDACs from the nucleus to the cytoplasm in a CRM1-dependent fashion (14,21,30,31,48).CaMK signaling to class II HDACs governs the activity of th...

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“…Sato and Funder 72 demonstrated PKC-dependent, aldosterone-induced hypertrophy in neonatal myocytes that was enhanced by elevated serum glucose and opposed by corticosterone. More recent studies have shown that cardiac hypertrophic markers (eg, natriuretic peptide precursor type A and B) and ␣-actin 1 are clearly increased in rat cardiac myocytes in response to aldosterone and involve phosphorylation of protein kinase D. 75 A number of other intracellular signaling pathways can also be upregulated by aldosterone, including PI3-kinase-p100␦, which promotes expression of the collagen genes COL1A1, COL1A2, and COL3A1, transforming growth factor-␤1 (TGF-␤1) in rat cardiac fibroblasts (a known profibrotic factor), connective tissue growth factor, 76 and plasminogen activator inhibitor. 77 Regulation of these pathways often has several levels of complexity; for example, upregulation of connective tissue growth factor is mediated by MR activation, the p38 MAPK pathway, and interactions between the 2.…”

Section: Fuller and Youngmentioning

confidence: 99%

“…Studies in the cardiac troponin T-Q92 transgenic mouse model of human hypertrophic cardiomyopathy (HCM) suggest that aldosterone is a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signals the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM. 75 Whether or not aldosterone acts directly on cardiac fibroblasts is unclear, with some investigators showing direct anabolic effects (collagen production), 80 whereas others have not. 81 Recently, Pratt et al suggested that aldosterone can promote proliferation of cardiac fibroblasts by activating specific cellular signaling cascades such as k-Ras and the MAPK1/2 cascade.…”

Section: Fuller and Youngmentioning

confidence: 99%

Mechanisms of Mineralocorticoid Action

Fuller¹,

Young²

2005

Hypertension

280

169

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Abstract-Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum-and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4 -2, a ubiquitin protein ligase; serum-and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4 -2, thereby rendering it unable to bind the sodium channels. Key Words: aldosterone Ⅲ sodium channels Ⅲ fibrosis T he isolation of aldosterone just over 50 years ago established it as the primary physiological mineralocorticoid. 1 Sodium transport, and hence salt balance, is regulated by a number of mechanisms; however, aldosterone has a critical role. Aldosterone exerts its effects on the distal nephron (and colon) as the last point of sodium reabsorption; it is thus the final arbiter. 2,3 The importance of aldosterone in the maintenance of sodium homeostasis is seen in a series of monogenetic causes of hypertension, 2 in Conn's syndrome, and in disorders in which mineralocorticoid action is compromised with consequent, life-threatening salt losses. 3 Although other pathophysiological consequences of aldosterone excess were identified by Selye 4 over 60 years ago, their significance has only recently been appreciated. Evidence from the Randomized ALdactone Evaluation Study (RALES) and EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS) trials of beneficial effects of mineralocorticoid antagonist therapy on morbidity and mortality in cardiac failure has focused attention beyond the kidney to effects of mineralocorticoids more broadly in the cardiovascular system. 5 Although an understanding of the molecular basis of aldosterone action has tended to lag behind advances in the biology of other steroid hormones, the last decade has seen significant advances toward an understanding of the mechanisms of mineralocorticoid action. The primary mediator of the response to aldosterone is the mineralocorticoid receptor (MR), the ligand-binding domain (LBD) of which has been recently crystallized. 6 -8 Although the MR primarily acts as a transcription factor, recent evidence suggests that it may also mediate nongenomic (or nonnuclear) activation of second messenger pathways. In addition, there is a growing body of evidence that some actions of aldosterone may involve a receptor other than the MR. The cellular and molecular mediators, including proteins induced by aldosterone, have been characterized in sodium transporting epithelia; however, the critical molecular events in the vasculature remain to be determined. In this brief r...

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Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy

Cited by 217 publications

References 54 publications

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Mechanisms of Mineralocorticoid Action

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