Microtubule Depolymerization Normalizes In Vivo Myocardial Contractile Function in Dogs With Pressure-Overload Left Ventricular Hypertrophy

Koide, Masaaki; Hamawaki, Masayoshi; Narishige, Takahiro; Sato, Hiroshi; Nemoto, Shintaro; DeFreyte, Gilberto; Zile, Michael R.; Cooper, George; Carabello, Blasé A.

doi:10.1161/01.cir.102.9.1045

Cited by 72 publications

(53 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There is evidence that microtubule densification contributes to contractile dysfunction through mechanical impairment of contractility (15,36,41). Reducing the viscous load upon myofilaments imposed by microtubules in the heart may allow AMPK to improve contractile function without additional energy expenditure.…”

Section: Discussionmentioning

confidence: 99%

“…Microtubules act as structural elements that resist actomyosin contractility (36) and also serve as tracks for transport of mRNA (25), proteins (16,32), and organelles (17,42). Although microtubules play important roles in many cell functions, stabilization and aberrant accumulation of microtubules in cardiomyocytes is a feature of pressure overload hypertrophy that may impair contractile function and contribute to heart failure (15,41). Aberrant stabilization and accumulation of MTs are believed to contribute to contractile dysfunction, in part, by increasing the viscous load on the myofilaments (36,41).…”

mentioning

confidence: 99%

See 1 more Smart Citation

AMPK attenuates microtubule proliferation in cardiac hypertrophy

Fassett

Xu³

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Cell hypertrophy requires increased protein synthesis and expansion of the cytoskeletal networks that support cell enlargement. AMPK limits anabolic processes, such as protein synthesis, when energy supply is insufficient, but its role in cytoskeletal remodeling is not known. Here, we examined the influence of AMPK in cytoskeletal remodeling during cardiomyocyte hypertrophy, a clinically relevant condition in which cardiomyocytes enlarge but do not divide. In neonatal cardiomyocytes, activation of AMPK with 5-aminoimidazole carboxamide ribonucleotide (AICAR) or expression of constitutively active AMPK (CA-AMPK) attenuated cell area increase by hypertrophic stimuli (phenylephrine). AMPK activation had little effect on intermediate filaments or myofilaments but dramatically reduced microtubule stability, as measured by detyrosinated tubulin levels and cytoskeletal tubulin accumulation. Importantly, low-level AMPK activation limited cell expansion and microtubule growth independent of mTORC1 or protein synthesis repression, identifying a new mechanism by which AMPK regulates cell growth. Mechanistically, AICAR treatment increased Ser-915 phosphorylation of microtubule-associated protein 4 (MAP4), which reduces affinity for tubulin and prevents stabilization of microtubules (MTs). RNAi knockdown of MAP4 confirmed its critical role in cardiomyocyte MT stabilization. In support of a pathophysiological role for AMPK regulation of cardiac microtubules, AMPK α2 KO mice exposed to pressure overload (transverse aortic constriction; TAC) demonstrated reduced MAP4 phosphorylation and increased microtubule accumulation that correlated with the severity of contractile dysfunction. Together, our data identify the microtubule cytoskeleton as a sensitive target of AMPK activity, and the data suggest a novel role for AMPK in limiting accumulation and densification of microtubules that occurs in response to hypertrophic stress.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

AMPK attenuates microtubule proliferation in cardiac hypertrophy

Fassett

Xu³

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Enhanced microtubules polymerization is associated with the development and progression of myocardial hypertrophy (Ishibashi et al 1996). Moreover, contractile dysfunction of hypertrophied cardiomyocytes is in parallel with the increase in microtubule polymerization, while microtubule depolymerization restores contractile function (Ishibashi et al 1996;Tsutsui et al 1999;Koide et al 2000). However, the pathogenic link between microtubule polymerization and myocardial apoptosis remains largely unknown.…”

Section: Immunoblotting For Bax/bcl-2mentioning

confidence: 99%

Colchicine, a Microtubule Depolymerizing Agent, Inhibits Myocardial Apoptosis in Rats

Fukumoto

Suzuki

et al. 2007

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Heart failure is the most common cardiovascular disease with high mortality and morbidity. Both enhanced microtubule polymerization and cardiomyocyte apoptosis are involved in the pathogenesis of heart failure. However, the link between the two mechanisms remains to be elucidated. In this study, we thus address this important issue in cultured cardiomyocytes from Wistar rats in vitro and in angiotensin II (ATII)-infused rats in vivo. Confocal microscopy examination showed that in cultured rat cardiomyocytes, micrographic density of microtubules was increased by paclitaxel, a microtubule-polymerizing agent, and decreased by colchicine, a microtubule-depolymerizing agent, but not affected by ATII, isoproterenol, or tumor necrosis factor-α alone. Immunoblotting analysis showed that Bax/Bcl-2 ratio, which is associated with the activation of caspase-3, was significantly increased in ATII-stimulated cultured cardiomyocytes in vitro and in ATII-infused rats in vivo, both of which were inhibited by co-treatment with colchicine. Caspase-3 and TUNEL assay to detect apoptosis in vitro demonstrated that paclitaxel or ATII alone significantly enhanced and their combination further accelerated cardiomyocyte apoptosis, which was again significantly inhibited by colchicine. Caspase-3 and TUNEL assay in vivo also demonstrated that ATII infusion significantly increased myocardial apoptosis and that co-treatment with colchicine significantly suppressed the apoptosis. In conclusion, these results indicate that a microtubule-depolymerizing agent could be a potential therapeutic strategy for treatment of heart failure.

show abstract

“…To move this story further toward clinical relevance, the hypothesis was now tested directly, again via a collaborative effort with B. A. Carabello and M. R. Zile, in the intact dog with a surgical model of aortic stenosis (19). Figure 11 compares LV contractile function and myocardial free and polymerized tubulin in a dog with severe aortic stenosis with these same variables in a normal dog.…”

Section: Does This Apply To the LV In Vivo?mentioning

confidence: 99%

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

Cooper

2006

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

Microtubule Depolymerization Normalizes In Vivo Myocardial Contractile Function in Dogs With Pressure-Overload Left Ventricular Hypertrophy

Abstract: These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload-induced cardiac hypertrophy.

Cited by 72 publications

References 37 publications

AMPK attenuates microtubule proliferation in cardiac hypertrophy

AMPK attenuates microtubule proliferation in cardiac hypertrophy

Colchicine, a Microtubule Depolymerizing Agent, Inhibits Myocardial Apoptosis in Rats

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

Contact Info

Product

Resources

About