Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure

Gallo, Pasquale; Latronico, Michael V.G.; Gallo, Paolo; Grimaldi, Séréna; Borgia, Francesco; Todaro, Matilde; Jones, Philip; Gallinari, Paola; Francesco, Raffaele De; Ciliberto, Gennaro; Steinkühler, Christian; Esposito, Giovanni; Condorelli, Gianluigi

doi:10.1093/cvr/cvn215

Cited by 145 publications

(104 citation statements)

References 41 publications

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“…8- 12 We also demonstrated that HDAC inhibitors reverse established hypertrophy. 10 In follow-up studies, we elucidated that activation of HDAC2, a class I HDAC, plays a key role in the development of hypertrophy, 13 which suggests a novel therapeutic role of histone modifiers in detrimental cardiac diseases.…”

mentioning

confidence: 75%

Sodium Valproate, a Histone Deacetylase Inhibitor, but Not Captopril, Prevents Right Ventricular Hypertrophy in Rats

Cho¹,

Eom

Kee

et al. 2010

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp lthough primary cardiac hypertrophy can result from genetic abnormalities, most cases in the clinical situation are secondary to pressure or volume overload, to mutations of sarcomere proteins, or to loss of contractile mass because of a prior infarction. 1 When cardiac hypertrophy persists for a long time without intensive care, the resulting deterioration in diastolic function often leads to congestive heart failure. 2 Great advances in surgical techniques and medical management of congenital heart diseases have dramatically improved the survival of affected patients over the past decades. However, with many patients with congenital heart disease now surviving until adulthood, right ventricular hypertrophy (RVH) has drawn much attention. 3 It is well known that several congenital heart diseases often cause RVH, even though various surgical or interventional corrections have been developed. Examples are pressure overload RVH caused by right ventricular (RV) outflow tract obstruction after total correction of tetralogy of Fallot, pulmonary stenosis, the atrial switch operation for transposition of the great arteries, and congenitally corrected transposition of the great arteries, and systemic RVH after the Fontan operation. Other conditions are volume overload RVH caused by atrial septal defect, tricuspid regurgitation, and pulmonary regurgitation. 3,4 Development of RVH should be carefully monitored and both medical prevention and treatment should be considered.Currently, afterload-reducing agents, β-adrenergic blockers, inotropics, and diuretics are used in the treatment of cardiac dysfunction, including cardiac hypertrophy. It is widely accepted that several angiotensin-converting enzyme (ACE) inhibitors have clinical benefits in the treatment of left ventricular hypertrophy (LVH) 5-7 but there is much debate over the ideal medical management of RVH 4 because the primary

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confidence: 75%

Sodium Valproate, a Histone Deacetylase Inhibitor, but Not Captopril, Prevents Right Ventricular Hypertrophy in Rats

Cho¹,

Eom

Kee

et al. 2010

Circ J

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“…Myofibroblast is characterized by de novo expression of ␣-SMA and the overproduction of interstitial matrix components such as fibronectin (47,53). It has been reported that HDAC activity is required for cardiac hypertrophy (13,21) and STAT3 is activated in the kidney after UUO injury (24). Thus we assessed the effect of TSA, a specific inhibitor of HDACs (4, 34) and AG490, a selective inhibitor of the STAT3 pathway (33), on the expression of ␣-SMA and fibronectin in a rat renal interstitial fibroblast cell line (NRK-49F).…”

Section: Resultsmentioning

confidence: 99%

“…TSA also blocked TGF-␤1-induced epithelial-to-mesenchymal transition (EMT) in renal tubular epithelial cells (51). Furthermore, administration of TSA attenuated cardiac hypertrophy induced by pressure overload and angiotensin II (13,21) and reversed atrial fibrosis and arrhythmia vulnerability in mice and/or rats (30). Despite the importance of HDACs in mediating cardiac hypertrophy, it remains unexplored whether HDAC activity is required for activation of renal interstitial fibroblasts and development of renal fibrosis.…”

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confidence: 99%

Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

Pang¹,

Kothapally²,

Mao

et al. 2009

American Journal of Physiology-Renal Physiology

189

202

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Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) . α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.

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“…Indeed, pan-HDAC inhibitors reduce cardiac hypertrophy due to pressure overload stimulation, angiotensin II infusion, or isoproterenol in rodent models (128)(129)(130). This effect may be more specific to HDAC1, -2, or -3, as the more selective class I HDAC inhibitor apicidin suppresses cardiac hypertrophy and improves function in a mouse model of pressure overload (131). HDAC inhibitors also reduce fibrosis and negative remodeling of the heart after myocardial infarction injury in the rat, as well as in rat models of spontaneous and salt-sensitive hypertension (132)(133)(134).…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Signaling effectors underlying pathologic growth and remodeling of the heart

2013

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Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

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Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure

Abstract: The apicidin derivative, API-D, is capable of reducing hypertrophy and, consequently, the transition to heart failure in mice subjected to TAC. Treatment with this substance, therefore, holds promise as an important therapeutic option for heart failure.

Cited by 145 publications

References 41 publications

Sodium Valproate, a Histone Deacetylase Inhibitor, but Not Captopril, Prevents Right Ventricular Hypertrophy in Rats

Sodium Valproate, a Histone Deacetylase Inhibitor, but Not Captopril, Prevents Right Ventricular Hypertrophy in Rats

Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

Signaling effectors underlying pathologic growth and remodeling of the heart

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