Lahouaria Hadri, PhD

Funded the The James and Marlene Ryan Innovation Award

Pulmonary arterial hypertension is a deadly disease characterized by abnormally high blood pressure in the pulmonary artery blood vessels. Pulmonary arterial hypertension occurs when the PA vascular cells overgrow and narrow their diameter, thus increasing the resistance to blood flow. This leads to right ventricle sided heart damage and eventually death. Understanding the role of the protein called ARID1a and the mechanisms underlying the regulation of an enzyme called EZH2 in the pulmonary artery vascular smooth muscle cells (PASMC) is critical in this deadly disease. We will use pulmonary arterial hypertension lung samples, PASMCs, and animal models to confirm the importance of the link between ARID1a and EZH2. We will also test inhaled drugs that inhibit the EZH2 activity to reduce PASMC overgrowth and potential right ventricle damage and failure in mice lacking the ARID1a gene. This will be crucial in defining whether drugs targeting EZH2 could be used to treat patients with pulmonary arterial hypertension. 

Update:  

Our findings suggest that ARID1a loss disrupts the regulation of genes involved in enhancing cell function and promotes abnormal growth of smooth muscle cells in pulmonary arterial hypertension (PAH) by altering how DNA is accessed and modified. Additionally, because ARID1a and EZH2 have opposing functions, ARID1a loss makes cells more sensitive to certain EZH2 inhibitors. This study represents the first exploration of ARID1a's role in PAH, revealing reduced ARID1a levels in lung samples from both PAH patients and animal models of pulmonary hypertension. In laboratory settings, ARID1a is shown to inhibit the proliferation of human pulmonary artery smooth muscle cells (hPASMC) and decrease EZH2 expression.