Basis for Increased Microtubules in Pressure-Hypertrophied Cardiocytes

Tagawa, Hirofumi; Rozich, John D.; Tsutsui, Hiroyuki; Narishige, Takahiro; Kuppuswamy, Dhandapani; Sato, Hiroshi; McDermott, Paul J.; Koide, Masaaki; Cooper, George

doi:10.1161/01.cir.93.6.1230

Cited by 66 publications

(69 citation statements)

References 39 publications

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“…Microtubule (MT)-based processes were more pronounced in LCR than HCR. This can be related to our findings of elevated blood pressure (52) and pathological cardiac growth in LCR, since increased MT density and increased level of MT binding proteins are associated with pressure overload cardiac hypertrophy (9,40,45). MTs are also involved in hypoxic signaling, which was found to be different in HCR and LCR.…”

Section: Discussionsupporting

confidence: 66%

Aerobic capacity-dependent differences in cardiac gene expression

Bye

Langaas

Høydal

et al. 2008

Physiological Genomics

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Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and cardiac gene expression we examined genome-wide gene expression in hearts of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in human, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in these animals. Left ventricle gene expression of both sedentary and exercise-trained HCR and LCR was characterized by microarray and gene ontology analysis. Out of 28,000 screened genes, 1,540 were differentially expressed between sedentary HCR and LCR. Only one gene was found differentially expressed by exercise training, but this gene had unknown name and function. Sedentary HCR expressed higher amounts of genes involved in lipid metabolism, whereas sedentary LCR expressed higher amounts of the genes involved in glucose metabolism. This suggests a switch in cardiac energy substrate utilization from normal mitochondrial fatty acid ␤-oxidation in HCR to carbohydrate metabolism in LCR, an event that often occurs in diseased hearts. LCR were also associated with pathological growth signaling and cellular stress. Hypoxic conditions seemed to be a common source for several of these observations, triggering hypoxia-induced alterations of transcription. In conclusion, inborn high vs. low aerobic capacity was associated with differences in cardiac energy substrate, growth signaling, and cellular stress. metabolic syndrome; metabolism; hypoxia; V O2max; hypertrophy ALTHOUGH MAXIMAL OXYGEN UPTAKE (V O 2max ) is statistically linked with cardiovascular mortality (23, 36), the mechanistic nature of this association is unknown and difficult to explore in humans. Specifically, it is well defined that the continuum of heart function is linearly related with the level of V O 2max (39). Within the gene-environment interactions, inheritance may account for as much as 70% of the variation in aerobic capacity in human (7). Hence, genetic predisposition and inborn aerobic capacity are likely to contribute toward cardiovascular disease and mortality.Rats with different inborn running capacities have been artificially selected over generations to generate strains with genetically determined high or low intrinsic capacity (25). The evolved strains of high capacity runners (HCR) and low capacity runners (LCR) have a 30% difference in V O 2max (17). Selecting for low running capacity also resulted in accumulation of risk factors that predispose to cardiovascular disease. That is, LCR have features of the metabolic syndrome, whereas HCR show an athletic phenotype with markedly better cardiac and vascular function relative to LCR (17, 52). These models were generated expressly for efficient and invasive evaluation of cardiometabolic disease that can lea...

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Section: Discussionsupporting

confidence: 66%

Aerobic capacity-dependent differences in cardiac gene expression

Bye

Langaas

Høydal

et al. 2008

Physiological Genomics

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“…In addition, previous studies have reported that hypertrophy-induced microtubule network expansion can sequester Smad3, preventing it from being accessed and phosphorylated by the transforming growth factor-β receptor. 37,38 This might explain although transforming growth factor-β expression was increased in Pak1-deficient hypertrophied hearts, yet it still failed to phosphorylate Smad3.…”

Section: Discussionmentioning

confidence: 99%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

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Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC -286 -binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

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“…Because increases in both RV mass and RV cardiomyocyte microtubule network density stabilize by 2 wk after PAB placement (49), for the period of 2 wk through 4 wk after surgery there was either no further treatment in half of the PAB cats or treatment by pilling with the nonselective ␤-adrenergic blocker propranolol HCl extended release (40 mg po b.i.d.) in the other half of the PAB cats.…”

Section: Methodsmentioning

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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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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Basis for Increased Microtubules in Pressure-Hypertrophied Cardiocytes

Abstract: Because we find persistent increases both in microtubules and in their biosynthetic precursors in pressure-hypertrophied myocardium, the mechanisms for this cytoskeletal abnormality must be sought through studies of the control both of microtubule stability and of tubulin synthesis.

Cited by 66 publications

References 39 publications

Aerobic capacity-dependent differences in cardiac gene expression

Aerobic capacity-dependent differences in cardiac gene expression

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

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

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