Right Ventricular Hypertrophy is Associated with Increased MAPK8, Fibronectin, and Extracellular Matrix Regulatory Biomarker (MMP/TIMP) mRNA Levels in a Pre‐Clinical Swine Model of HFpEF

Abstract

A prominent characteristic of heart failure with preserved ejection fracture (HFpEF) is diastolic dysfunction of the left ventricle. However, approximately one‐third of HFpEF patients also demonstrate right ventricular (RV) dysfunction. Although RV dysfunction in HFpEF is associated with decreased survival, little research examining this issue has been conducted. The goal of this study was to identify molecular mechanisms underlying RV remodeling in a new pre‐clinical Ossabaw swine model with potential relevance to HFpEF. RNA‐seq and Ingenuity Pathway Analysis (IPA) was performed on three RV samples from each of the following groups: 1) lean control (CON; N=4); and 2) Western Diet‐fed aortic‐banded heart failure (WD‐AB; N=4). Module Enrichment Analysis was performed on all expressed and varying genes, and networks were generated using IPA. Significant genetic signatures identified with IPA were validated using qRT‐PCR, and group comparisons were made using a student's t‐test with significance reported at the P < 0.10 and P < 0.05 levels. Postmortem RV weight was significantly increased in the WD‐AB group compared to CON, thus, we hypothesized gene networks associated with RV hypertrophic remodeling would be activated in WD‐AB animals. IPA found Cardiac Hypertrophy and Cardiac Fibrosis as the #2 and #3 top significant Toxicology Lists. Gene interactions within these lists indicated enrichment of a network driven by mitogen‐activated protein kinase 8 (MAPK8, also known as JNK1). Subsequent analysis by qRT‐PCR indicated a significant increase in MAPK8 mRNA levels in WD‐AB animals compared to CON, validating RNA‐seq findings. Activation of MAPK8 is associated with selective extracellular matrix (ECM) remodeling characterized by an increase in fibronectin, but not collagen, deposition. Further molecular interrogation supported this concept, as RV fibronectin mRNA levels were significantly increased in the WD‐AB group compared to CON with no change observed in Collagen I or III isoforms. Fibronectin and MAPK8 mRNA levels were also significantly positively correlated to postmortem RV weight. RV fibrotic remodeling was further associated with alterations to regulatory biomarkers of the ECM including increased mRNA levels of matrix metalloproteinase 2 and 9 (MMP2/MMP9) and tissue inhibitor of metalloproteinase 1 and 4 (TIMP1/TIMP4). In conclusion, these results suggest pathological RV hypertrophy occurs via two potential mechanisms: 1) selective fibrotic remodeling of the ECM through MAPK8‐mediated signaling and fibronectin accumulation; and 2) altered levels of the ECM regulatory biomarkers MMP2/MMP9 and TIMP1/TIMP4 in a preclinical swine model with potential relevance to HFpEF.Support or Funding InformationHL112998 (CAE); VA‐Merit I01BX003271 (RSR); HL125503 (JP); HL136292 (TLD); HL122737, HL123295, & HL129639 (YW)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.