Restoration of Impaired Endothelial MEF2 Function Rescues Pulmonary Arterial Hypertension

Study Questions:

What is the role of myocyte enhancer factor 2 (MEF2) in pulmonary arterial hypertension (PAH)?

Methods:

The transcription factor, MEF2, was studied in pulmonary artery endothelial cells (PAECs) from subjects with PAH. Pharmacologic manipulation of MEF2 was studied in PAECs and in rat models of PAH.

Results:

MEF2 activity was significantly impaired in PAECs derived from PAH subjects. MEF2 was found to be a key regulator of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexin 37and 40, and KLF2 and KLF4, which were found to be decreased in PAH PAECs. Impaired MEF2 activity was mediated by excess nuclear accumulation of two class IIa histone deacetylases (HDACs) that inhibit its function, HDAC4 and HDAC5. 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 models.

Conclusions:

The authors concluded that strategies to augment MEF2 activity hold potential therapeutic value in PAH. Selective HDAC IIa inhibition may be a viable alternative approach to avoid the potential adverse effects of broad-spectrum HDAC inhibition in PAH.

Perspective:

PAH is characterized by the abnormal proliferation of pulmonary artery vascular cells, which leads to obliterative vasculopathy with increased pulmonary vascular resistance. Despite advances in vasodilator therapies, prognosis remains poor. Therapies targeting the underlying vascular proliferative response may be particularly useful. The current study demonstrates the potential importance of the transcriptional regulator, MEF2, in regulating this abnormal proliferation. Importantly, MEF2 activity can be restored with selective HDAC inhibition, which will be safer than global HDAC inhibition. Additional studies to confirm these findings and explore other potential targets in these pathways will facilitate clinical application of this approach.

Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension

Keywords: Histone Deacetylase Inhibitors, MEF2 Transcription Factors, Hypertension, Pulmonary, Vascular Resistance, MicroRNAs, Homeostasis, Connexins, Pulmonary Artery, Endothelial Cells, Cell Movement, Repressor Proteins, Vasodilator Agents


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