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

Abstract

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...

Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

“…Few studies have reported the beneficial effects of small molecule inhibitors of class I HDACs in preclinical models of LV and RV failure, blocking pathological cardiac hypertrophy and fibrosis and improving ventricular function [25]. Contrary to initial findings of the beneficial effects of HDAC inhibition using VPA on pulmonary artery banding (PAB) or MCT-induced cardiac hypertrophy [26] and trichostatin A (TSA) on transverse aortic constriction-induced cardiac hypertrophy [27], BOGAARD et al [28] reported detrimental effects of TSA and VPA treatment in PAB-induced RV hypertrophy.…”

Suberoylanilide hydroxamic acid attenuates paraquat-induced pulmonary fibrosis by preventing Smad7 from deacetylation in rats

“…SAHA has been shown to inhibit the deacetylase activity of HDAC1, 2, 3, 6, 8 (27). HDAC1 was confirmed that it's the strongest deacetylase to deacetylate Smad7 (11 Figure 4A) in a time-dependent manner.…”

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

“…Indeed, estrogen through ERβ can activate the modulatory calcineurin-interacting protein 1 gene blocking calcineurin activation in myocytes 22 . Histone deacetylase (HDACs) are important in regulation of cardiac hypertrophy: class II is involved in signaling that inhibit this disorder, whereas class I promotes hypertrophy 106 . Recently, Pedram at al demonstrated that angiotensin regulates gene and protein level of both class I and II HDACs and rapid estrogen action through ERβ blocks these angiotensin actions 107 .…”