Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction

Cooper, IV George

doi:10.1152/ajpheart.00132.2006

Cited by 68 publications

(50 citation statements)

References 28 publications

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“…*P Ͻ 0.05 for difference from control; †P Ͻ 0.05 for difference from PAB by 1-way ANOVA with Bonferroni post hoc analysis. subsequent work in this area (11), and here, although there is transient STAT3 recruitment to the cytoskeleton at 2 days after pressure overloading (54), this is no longer significant by 1 wk after pressure overloading when the characteristic indefinitely persistent dense microtubule network is just beginning to form (49). Thus it is not clear that STAT3 has a causal role in producing and more especially in maintaining the hypertrophyrelated dense cardiac microtubule network.…”

Section: Why Was It Important To Do This Study?mentioning

confidence: 69%

“…This cytoskeletal alteration becomes more pronounced during the deterioration of initially compensatory right ventricular (RV) or left ventricular (LV) pressure overload hypertrophy into the congestive heart failure state, both in animal models of human disease (47,48) and in human disease itself (58). In addition to contributing to the systolic and diastolic contractile dysfunction that is characteristic of pathological hypertrophy (11), the extensive decoration of cardiomyocyte microtubules with myocardial microtubule-associated protein (MAP)4 that was found to cause this microtubule network densification by stabilizing the microtubules (43) was also found to inhibit the kinesin-based transport of mRNA along microtubules that is required to support the translation of myofibrillar proteins (44). Thus this dense, heavily MAP-decorated microtubule network appears not only to contribute to the progressive contractile dysfunction that is characteristic of pathological hypertrophy but also to undermine the very basis for the compensatory hypertrophic growth response itself.…”

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confidence: 99%

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Cytoskeletal role in protection of the failing heart by β-adrenergic blockade

Cheng

Kasiganesan

Baicu

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Formation of a dense microtubule network that impedes cardiac contraction and intracellular transport occurs in severe pressure overload hypertrophy. This process is highly dynamic, since microtubule depolymerization causes striking improvement in contractile function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1 and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant myocardial microtubule-associated protein (MAP)4, which then decorates and stabilizes microtubules. This persistent phosphatase activation is dependent upon ongoing upstream activity of p21-activated kinase-1, or Pak1. Because cardiac ␤-adrenergic activity is markedly and continuously increased in decompensated hypertrophy, and because ␤-adrenergic activation of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on ␤-adrenergic overdrive and thus could be reversed by ␤-adrenergic blockade. The data in this study, which were designed to answer this question, show that such is the case; that is, ␤ 1-(but not ␤ 2-) adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network. These data were gathered in a feline model of severe right ventricular (RV) pressure overload hypertrophy in response to tight pulmonary artery banding (PAB) in which a stable, twofold increase in RV mass is reached by 2 wk after pressure overloading. After 2 wk of hypertrophy induction, these PAB cats during the following 2 wk either had no further treatment or had ␤-adrenergic blockade. The pathological microtubule phenotype and the severe RV cellular contractile dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed in the treated (PAB ␤-Blockade) cats. Thus these data provide both a specific etiology and a specific remedy for the abnormal microtubule network found in some forms of pathological cardiac hypertrophy. microtubule; hypertrophy; heart failure IN 1993 A UNIQUE CYTOSKELETAL alteration was reported in the hypertrophying heart (51, 52). It was discovered that in myocardium hypertrophying in response to pathological pressure overloading, but not in response to an equivalent degree and duration of physiological volume overloading, there is a persistent increase in microtubule network density that causes contractile dysfunction. This cytoskeletal alteration becomes more pronounced during the deterioration of initially compensatory right ventricular (RV) or left ventricular (LV) pressure overload hypertrophy into the congestive heart failure state, both in animal models of human disease (47, 48) and in human disease itself (58). In addition to contributing to the systolic and diastolic contractile dysfunction that is characteristic of pathological hypertrophy (11), the extensive decoration of cardiomyocyte microtubules wi...

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Section: Why Was It Important To Do This Study?mentioning

confidence: 69%

mentioning

confidence: 99%

Cytoskeletal role in protection of the failing heart by β-adrenergic blockade

Cheng

Kasiganesan

Baicu

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…RV remodeling in response to increased afterload is a complex process that involves 1) changes in expression of cytoskeletal proteins in cardiac myocytes, 2) increase in cardiomyocyte size, and 3) proliferation of noncardiomyocytes in the myocardium (12,13,58). Emerging studies suggest that miRs play a critical role in regulating expression of proteins that are involved in gene regulation, cell proliferation, and cell apoptosis (8,29).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

Joshi

Dhagia

Gairhe

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Joshi SR, Dhagia V, Gairhe S, Edwards JG, McMurtry IF, Gupte SA. MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 311: H689 -H698, 2016. First published July 15, 2016 doi:10.1152/ajpheart.00264.2016.-Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR- 21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (Ͼ2-fold; P Ͻ 0.05) in the right ventricle (RV) of PAH compared with normal rats; 2) miR-31-5 and 3p, and miR-208b-3p were upregulated (Ͼ2-fold; P Ͻ 0.05) in the left ventricle plus septum (LVϩS) of PAH compared with normal rats; 3) miR-187-5p, miR-208a-3p, and miR-877 were downregulated (Ͼ2-fold; P Ͻ 0.05) in the RV of PAH compared with normal rats; and 4) no miRs were up-or downregulated with Ͼ2-fold in LVϩS compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LVϩS of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.Listen to this article's corresponding podcast at http://ajpheart. podbean.com/e/mir140-and-right-heart-hypertrophy/. miR; heart; hypertrophy; heart failure; pulmonary; hypertension; lungs; rats THE PATHOPHYSIOLOGY of pulmonary arterial hypertension (PAH) is heterogeneous. In PAH, pulmonary vascular resistance and arterial pressure are increased, and the right ventricle (RV) is hypertrophied in response to increased afterload/pressure overload. Increased afterload in PAH leads to myocardial dysfunction, tricuspid regurgitation with progressive annular dilatation, and ultimately RV failure (67).Heart failure, a major cause of mortality in PAH patients (4, 5), is a complex syndrome. In the failing hearts, oxidative stress is increased and the rate of cardiomyocyte apoptotic and autophagic death is augmented (6,49,51,60,62). Activation of these processes causes myocardial stiffening, dilatation, and loss of contractility (49, 51). However, the mechanisms that regulate apoptosis and autophagy in this complex pathology are unclear and are an area under investigation.MicroRNAs (miRs) are a class of small no...

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“…Microtubules are dynamic structures that run longitudinally across the myocyte and are concentrated in the perinuclear regions (275). Under normal conditions, microtubules have small effects on the structural properties of cardiac myocytes (135,644). They appear to function primarily as a means of organizing particles, vesicles, and organelles within the myocyte.…”

Section: Microtubulesmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction

Abstract: Cooper, George IV. Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction.

Cited by 68 publications

References 28 publications

Cytoskeletal role in protection of the failing heart by β-adrenergic blockade

Cytoskeletal role in protection of the failing heart by β-adrenergic blockade

MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

Designing Heart Performance by Gene Transfer

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