Chronic Colchicine Administration Attenuates Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Tsutsui, Hiroyuki; Ishibashi, Yuji; Takahashi, Masaru; Namba, Takashi; Tagawa, Hirofumi; Imanaka‐Yoshida, Kyoko; Takeshita, Akira

doi:10.1006/jmcc.1999.0953

Cited by 25 publications

(21 citation statements)

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“…A sample size of 25 to 30 was targeted for 3 reasons: there were 3 groups in the analysis, to reduce effects of the heterogeneity with colchicine treatment, and to account for possible deaths during the experimental time frame. The dosing scheme was implemented as similar doses were shown to depolymerize the microtubule cytoskeleton in cardiomyocytes in rats23, 24 but less than doses that are associated with significant cardiotoxicity in rats 25. Four weeks after MCT injection was the end point of the study because a previous study had shown that time frame was associated with severe pulmonary hypertension 21…”

Section: Methodsmentioning

confidence: 99%

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Prins

Tian

et al. 2017

JAHA

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BackgroundPulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced PAH.Methods and ResultsImmunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.ConclusionsMonocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV‐directed therapy for PAH.

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Section: Methodsmentioning

confidence: 99%

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Prins

Tian

et al. 2017

JAHA

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“…Adenosine treatment reduced the accumulation of microtubules in vitro, whereas reduction of adenosine production by genetic deletion of CD73 increased cardiac microtubule accumulation and stability in vivo. Data from studies using microtubule-inhibiting drugs suggest that microtubule polymerization is required for hypertrophic growth (52,54,59), so it is possible that the effects of adenosine on microtubule stability may limit hypertrophy. However, the maladaptive densification of microtubules in response to pressure overload does not necessarily promote hypertrophy (48,55).…”

Section: Discussionmentioning

confidence: 99%

Adenosine regulation of microtubule dynamics in cardiac hypertrophy

Fassett

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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There is evidence that endogenous extracellular adenosine reduces cardiac hypertrophy and heart failure in mice subjected to chronic pressure overload, but the mechanism by which adenosine exerts these protective effects is unknown. Here, we identified a novel role for adenosine in regulation of the cardiac microtubule cytoskeleton that may contribute to its beneficial effects in the overloaded heart. In neonatal cardiomyocytes, phenylephrine promoted hypertrophy and reorganization of the cytoskeleton, which included accumulation of sarcomeric proteins, microtubules, and desmin. Treatment with adenosine or the stable adenosine analog 2-chloroadenosine, which decreased hypertrophy, specifically reduced accumulation of microtubules. In hypertrophied cardiomyocytes, 2-chloroadenosine or adenosine treatment preferentially targeted stabilized microtubules (containing detyrosinated α-tubulin). Consistent with a role for endogenous adenosine in reducing microtubule stability, levels of detyrosinated microtubules were elevated in hearts of CD73 knockout mice (deficient in extracellular adenosine production) compared with wild-type mice (195%, P < 0.05). In response to aortic banding, microtubules increased in hearts of wild-type mice; this increase was exaggerated in CD73 knockout mice, with significantly greater amounts of tubulin partitioning into the cold-stable Triton-insoluble fractions. The levels of this stable cytoskeletal fraction of tubulin correlated strongly with the degree of heart failure. In agreement with a role for microtubule stabilization in promoting cardiac dysfunction, colchicine treatment of aortic-banded mice reduced hypertrophy and improved cardiac function compared with saline-treated controls. These results indicate that microtubules contribute to cardiac dysfunction and identify, for the first time, a role for adenosine in regulating cardiomyocyte microtubule dynamics.

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“…Cardiomyocytes were incubated for 16 or 24 hrs in the presence or absence of apoptosis-inducing factors, such as angiotensin II (10 μ mol/L, Sigma Chemicals, St. Louis, MO, USA), isoproterenol (100 μ mol/L, Sigma Chemicals), or TNF-α (10 ng/mL, Sigma Chemicals) (n = 6~9), with or without co-treatment with a microtubule-polymerizing agent, paclitaxel (taxol, 10 μ mol/L, Bristol-Myers Squibb Co., Princeton, NJ, USA), or a depolymerizing agent, colchicine (10 μ mol/L, Sigma Chemicals) (n = 6~9), as previously described (Tsutsui et al 1999;Sharma and Singh 2000;Ishibashi et al 2003).…”

confidence: 99%

“…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.

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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.

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Chronic Colchicine Administration Attenuates Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Cited by 25 publications

References 0 publications

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Adenosine regulation of microtubule dynamics in cardiac hypertrophy

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

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