The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature

Abstract

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly two-fold increased risk of death compared to those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome dataset in the RV of a pre-clinical model of cardio-metabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, n=5) or Western Diet and aortic-banding (WD-AB; n=4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared to CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using Principal Component Analysis, Weighted Gene Co-Expression Network Analysis, Module Enrichment Analysis, and Ingenuity Pathway Analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardio-metabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.