Suppression of Histone Deacetylases Worsens Right Ventricular Dysfunction after Pulmonary Artery Banding in Rats

Bogaard, Harm Jan; Mizuno, Shiro; Hussaini, Ayser A. Al; Toldo, Stefano; Abbate, Antonio; Kraskauskas, Donatas; Kasper, Michael; Natarajan, Ramesh; Voelkel, Norbert F.

doi:10.1164/rccm.201007-1106oc

Cited by 146 publications

(166 citation statements)

References 32 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…Bogaard et al 75 hypothesized that the deleterious effects of TSA on the RV are due, at least in part, to its ability to reduce capillary density in the chamber of the heart. Indeed, HDAC inhibitors have been shown to elicit antiangiogenic effects through suppression of VEGF signaling in cancer models.…”

Section: Hdac Inhibitors In Models Of Ph and Rv Hypertrophymentioning

confidence: 99%

See 1 more Smart Citation

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

2015

View full text Add to dashboard Cite

Reversible lysine acetylation has emerged as a critical mechanism for controlling the function of nucleosomal histones as well as diverse nonhistone proteins. Acetyl groups are conjugated to lysine residues in proteins by histone acetyltransferases and removed by histone deacetylases (HDACs), which are also commonly referred to as lysine deacetylases. Over the past decade, many studies have shown that HDACs play crucial roles in the control of left ventricular (LV) cardiac remodeling in response to stress. Small molecule HDAC inhibitors block pathological hypertrophy and fibrosis and improve cardiac function in various preclinical models of LV failure. Only recently have HDACs been studied in the context of right ventricular (RV) failure, which commonly occurs in patients who experience pulmonary hypertension (PH). Here, we review recent findings with HDAC inhibitors in models of PH and RV remodeling, propose next steps for this newly uncovered area of research, and highlight potential for isoform-selective HDAC inhibitors for the treatment of PH and RV failure. Heart failure due to systolic and/or diastolic ventricular dysfunction afflicts approximately 6 million Americans, placing an economic burden on the United States that is projected to increase to nearly $100 billion annually by 2030. 1 Most preclinical studies of heart failure focus on the left ventricle (LV) of the heart, because LV failure causes death in the large populations of patients who experience conditions such as ischemic heart disease and resistant systemic hypertension. As such, significantly more is known about the molecular mechanisms governing LV failure than about those associated with right ventricular (RV) failure.In patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary circulation increases pulmonary vascular resistance and often results in RV failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, highlighting an urgent need for novel therapeutics. 2 Current standards-of-care (SOC) for patients with PH involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins. 3 It is hypothesized that more effective therapeutic strategies will be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 4 Importantly, maintenance of RV function is the key determinant of survival in patients with PH, and it is unclear whether SOC therapy for LV failure (e.g., β-blockers and angiotensin-converting enzyme inhibitors) is effective for RV failure. 5 Clearly, increased emphasis needs to be placed on elucidating pathogenic mechanisms in this chamber of the heart.Multiple small molecule inhibitors of histone deacetylase (HDAC) enzymes have been shown...

show abstract

Section: Hdac Inhibitors In Models Of Ph and Rv Hypertrophymentioning

confidence: 99%

“…Supplemental data from Bogaard et al 75 described effects of VPA in the rat PAB model. Importantly, although VPA appeared to cause a mild increase in RV inner diameter during diastole, it did not increase fibrosis or reduce capillary density; details regarding VPA dosing regimen were not provided.…”

Section: Hdac Inhibitors In Models Of Ph and Rv Hypertrophymentioning

confidence: 99%

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

2015

View full text Add to dashboard Cite

show abstract

“…For example, recent findings demonstrate that Trichostatin A and valproic acid protect from load-and agonist-induced cardiac hypertrophy in vivo [74,75]. However, contrasting findings indicate that Trichostatin A worsens right ventricular dysfunction induced by pulmonary artery banding in rats [76]. Given these potential complications, combinatorial effects of more selective or isoform-specific HDAC inhibitors with conventional therapeutics may provide a therapeutic advantage.…”

Section: Combinatorial Therapies With Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors

Ververis

Karagiannis

2012

ISRN Cell Biology

View full text Add to dashboard Cite

The important role of histone deacetylase enzymes in regulating gene expression, cellular proliferation, and survival has made them attractive targets for the development of histone deacetylase inhibitors as anticancer drugs. Suberoylanilide hydroxamic acid (Vorinostat, Zolinza), a structural analogue of the prototypical Trichostatin A, was approved by the US Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma in 2006. This was followed by approval of the cyclic peptide, depsipeptide (Romidepsin, Istodax) for the same disease in 2009. Currently numerous histone deacetylase inhibitors are undergoing preclinical and clinical trials for the treatment of hematological and solid malignancies. Most of these studies are focused on combinations of histone deacetylase inhibitors with other therapeutic modalities, particularly conventional chemotherapeutics and radiotherapy. The aim of this paper is to provide an overview of the classical histone deacetylase enzymes and histone deacetylase inhibitors with an emphasis on potential combination therapies.

show abstract

“…Treatment of pulmonary artery banded rats with broad spectrum HDACi resulted in right ventricle remodeling that was worse than in untreated animals. 44 The authors provided evidence that this may be due to the anti-angiogenic and/or pro-apoptotic effects of broad spectrum HDACi. 44 Hence, the use of HDACi could lead to severe unwanted side effects in situations where an adaptive angiogenic response to acute injury is required.…”

Section: Epigenetic-based Therapies In Fibrosismentioning

confidence: 99%

“…44 The authors provided evidence that this may be due to the anti-angiogenic and/or pro-apoptotic effects of broad spectrum HDACi. 44 Hence, the use of HDACi could lead to severe unwanted side effects in situations where an adaptive angiogenic response to acute injury is required. a process that is mediated by histone methyltransferases (HMTs).…”

Section: Epigenetic-based Therapies In Fibrosismentioning

confidence: 99%

Epigenetics within the matrix

Robinson

Watson²,

Baugh³

2012

Epigenetics

View full text Add to dashboard Cite

Suppression of Histone Deacetylases Worsens Right Ventricular Dysfunction after Pulmonary Artery Banding in Rats

Abstract: HDAC inhibition is associated with dysfunction and worsened remodeling of the pressure-overloaded RV. The detrimental effects of HDAC inhibition on the pressure-overloaded RV may come about via antiangiogenic or proapoptotic effects.

Cited by 146 publications

References 32 publications

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors

Epigenetics within the matrix

Contact Info

Product

Resources

About