Alternative Polyadenylation Signatures Distinguish Maladaptive Right Ventricular Remodeling in Pulmonary Hypertension: Implications for RNA-Based Diagnostics and Therapeutics

Increased pulmonary vascular pressures due to vascular remodeling, elevated vascular resistance, and vasoconstriction characterize Pulmonary Arterial Hypertension (PAH). The narrowing of the pulmonary arteries and obstruction of blood flow increase the Right Ventricular (RV) afterload, forcing the RV to undergo structural and functional changes. While adaptive remodeling leads to RV compensation by maintaining function, maladaptive remodeling leads to RV decompensation, characterized by worsening function and eventual failure. At present, there is no effective treatment for these patients as therapies for left ventricular failure are ineffectual, and there are no therapies specifically targeting the RV. Therefore, there is a clear need to understand the pathophysiology of RV failure and to identify the differences between adaptive and maladaptive RV remodeling. This study analyzes changes in polyadenylation site usage, a process known as alternative polyadenylation (APA), in RV failure. APA is a mechanism used to regulate mRNA maturation that can result in either shortening or elongation of the mRNA 3'UTR. By analyzing APA patterns in RV tissue from donor controls and patients with compensated and decompensated RV failure, we demonstrate a pattern of 3'UTR elongation that is present in decompensated RV failure and not in compensated or control RVs. Further, altered APA was also detected in 3 distinct rat models of PH, where 15 transcripts had shared APA alterations across both rat models and human disease. Our study provides an unbiased approach to identifying the molecular changes leading to RV dysfunction while pinpointing novel therapeutic targets that can be leveraged for intervention. These APA signatures may serve as biomarkers to distinguish adaptive from maladaptive RV remodeling. In addition, the RNA-processing machinery that regulates APA, such as NUDT21 and CPSF6, represents potential therapeutic targets for RNA-based interventions. Together, our findings link RNA processing to diagnostic and therapeutic opportunities in right heart failure.