Abstract 4363274: Evolutionarily Conserved Signatures of Adaptive Right Ventricular Remodeling

Abstract

Background: Right ventricular failure (RVF) has a high mortality risk across multiple heart diseases, has no proven therapies, and has few identified candidate targets suitable for testing in preclinical models. Research Goal: Identify evolutionarily conserved signatures of adaptive and maladaptive RV responses in human dilated cardiomyopathy (DCM) and mouse pulmonary artery band (PAB). Methods: Total and phosphoproteomics was performed for 56 human RVs (n= 16 nonfailing (NF), n=40 DCM) and 18 mice (n=6 sham, n=12 PAB). We used hemodynamic and echocardiographic assessments of DCM and PAB RVs to differentiate disease-associated from adaptive and maladaptive signatures by Voom/Limma, weighted correlation network analyses, and direct queries for sex-conserved patterns. We performed pathway enrichment analyses in Enrichr. Results: Right ventricular DCM and PAB differential protein abundances were broadly but modestly conserved (rho 0.34, P<0.0001) and revealed loss of mitochondrial/metabolic proteins and increase in extracellular matrix/TGFβ, collagen, and cell junction proteins. Adaptive/maladaptive signatures converged on actin and cell membrane remodeling, metabolic, proteostatic, and fibrotic proteins. Adaptive responses included increase in skeletal muscle ACTA1, enhanced sarcomeric actin treadmilling (e.g. CFL2), and cell membrane repair mechanisms (e.g. PARVA and TRIM72 phosphorylation). Whereas non-sarcomeric actin remodeling was maladaptive driven by a noncanonical WNT signaling axis involving small GTPases, WAVE2 complex, and ARP2/3. Loss/inhibition of oxidative phosphorylation, fatty acid oxidation, and malate-aspartate shuttle occurred in DCM/PAB independent of outcomes, whereas activation of pyruvate metabolism via downregulation of PDK1/4 and disinhibition of PDH1A was adaptive. Adaptive proteostatic signatures included slowed protein synthesis and enhanced folding, with mixed evidence for increase and decreased protein turnover involving autophagy, proteasome, and urea cycle. Maladaptive fibrotic signatures included stepwise increases in COL12A1, COL18A1, FN1, FMOD, LTBP2, and POSTN. Conclusion: Signatures of human adaptive RV remodeling that are conserved in mice—and therefore testable—include enhanced sarcomeric actin turnover, cell membrane repair, activation of pyruvate metabolism, and chaperone capacity exceeding protein synthetic needs.