Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary arterioles, characterized by increased pulmonary arterial pressure and right ventricular failure. The etiology of PAH is complex, but aberrant proliferation of the pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) is thought to play an important role in its pathogenesis. Understanding the mechanisms of transcriptional gene regulation involved in pulmonary vascular homeostasis can provide key insights into potential therapeutic strategies. Methods and Results We demonstrate that the activity of the transcription factor myocyte enhancer factor 2 (MEF2) is significantly impaired in the PAECs derived from subjects with PAH. We identified MEF2 as the key cis-acting factor that regulates expression of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexins 37, connexin 40, Krűppel Like Factor 2 (KLF2) and KLF4, which were found to be significantly decreased in PAH PAECs. The impaired MEF2 activity in PAH PAECs was mediated by excess nuclear accumulation of two class IIa histone deacetylases (HDACs) that inhibit its function, namely HDAC4 and HDAC5. Selective, pharmacologic inhibition of class IIa HDACs led to restoration of MEF2 activity in PAECs, as demonstrated by increased expression of its transcriptional targets, decreased cell migration and proliferation, and rescue of experimental pulmonary hypertension (PH) models. Conclusions Our results demonstrate that strategies to augment MEF2 activity holds potential therapeutic value in PAH. Moreover, we identify selective HDAC IIa inhibition as a viable alternative approach to avoid the potential adverse effects of broad spectrum HDAC inhibition in PAH.

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

“…Finally, correlating with increased PAEC proliferation, our findings revealed a promigratory phenotype promoted by matrix stiffness and the YAP-GLS1 axis ( Figure 6F). A disorder of proliferation and migration has been observed in human plexiform lesions (22), and more recent studies of hyperproliferative PAECs in PH have described an accompanying migratory phenotype (38). Such disordered migration may contribute to abnormal angiogenesis in PH -which in some cases has been linked to a proangiogenic and pathogenic remodeling of the pulmonary arteriole (39) and in other cases has been linked to a deficiency of angiogenesis (39) and a pruning of the entire pulmonary vascular tree.…”

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

“…Selective, pharmacological inhibition of class IIa HDACs using MC1568 restored myocyte enhancer factor 2 activity in IPAH PAECs and rescued from experimental PH (monocrotaline (MCT) and SU5416 plus hypoxia) with no RV fibrosis or coronary artery endothelial cell apoptosis [21]. However, a recent study reported that the class IIa HDAC inhibitor MC1568 moderately suppressed class IIb HDACs, but failed to inhibit class IIa HDAC catalytic activity on a class-selective synthetic substrate in rat left ventricular homogenates [23], while other studies report pan-inhibition of both class IIa and class IIb HDAC isoforms by MC1568 employing recombinant proteins on histones [24].…”

“…However, only three studies have reported evidence of aberrant gene or protein expression of HDAC isoforms in pulmonary tissues, including human lung homogenates (HDAC1, HDAC4 and HDAC5) [20], human PAH-PAECs (HDAC4 and HDAC5) [21] and from pulmonary adventitial fibroblasts from chronically hypoxic calves (HDAC1, HDAC2 and HDAC3) [9]. However, the pulmonary vascular cell-specific expression and molecular function of specific HDAC isoforms in health and disease remains to be thoroughly explored in PH.…”

“…Recently, KIM et al [21] demonstrated that myocyte enhancer factor 2 transcriptional activity was impaired in PAH PAECs mediated by the excess nuclear accumulation of HDAC4 and HDAC5. Selective, pharmacological inhibition of class IIa HDACs using MC1568 restored myocyte enhancer factor 2 activity in IPAH PAECs and rescued from experimental PH (monocrotaline (MCT) and SU5416 plus hypoxia) with no RV fibrosis or coronary artery endothelial cell apoptosis [21].…”

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

“…The impaired MEF2 activity in ECs from PAH was associated with increased nuclear accumulation of HDAC4 and HDAC5. So, increasing MEF2 activity by the selective inhibition of class IIa HDACs by MC1568 seems to suppress excessive EC migration and proliferation by PAH-ECs and can rescue experimental PAH model [106]. Although the increased migration and proliferation of pulmonary artery ECs in PAH are also hallmarks of angiogenesis, it is still contentious to link excessive angiogenesis with the pathogenesis of PAH [107], and any potential anti-angiogenic therapy for PAH should be proceeded with caution.…”