A MicroRNA-Based Therapeutic Approach for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH), a group of Pulmonary Hypertension (PH), is a disease characterized by progressive remodeling of the distal pulmonary arteries, resulting in the loss of vascular cross-sectional area and elevated pulmonary vascular resistance. Without intervention, PAH is usually progressive, leading to right heart failure and death. New directions and therapies that could improve understanding and treating PAH are desperately needed. MicroRNAs (miRs) are small non-coding RNAs that control expression of complementary target mRNAs. miR-32, reported to be the most upregulated microRNA in the lungs of PAH patients, was shown to promote cancer cell proliferation and migration. These findings prompted further functional characterization of this microRNA in the setting of PAH. Our goal is to attenuate pulmonary vascular remodeling by inhibiting miR-32 as a therapeutic approach to reverse the pathological changes in PAH. The specific aims of this proposal are to: 1) Assess the expression and regulation of miR-32 in PAH; 2) Investigate whether miR-32 is responsible for the differences observed between male and female PAH patients; 3) Evaluate the effects of miR-32 overexpression and inhibition on pulmonary vascular cells proliferation and migration; 4) Determine the in vivo effects of miR-32 inhibition on pulmonary vascular remodeling and PAH using mice and rat models of PAH; and 5) Identify the mechanisms of action of miR-32. Defining the regulation and the mechanisms of miR-32 and its physiological consequences will be of great relevance in the analysis of the PAH disease. Targeting miR-32 might be a useful strategy to treat pulmonary arterial hypertension.