A critical contribution of cardiac myofibroblasts in right ventricular failure and the role of UCP2 SNPs in the predisposition to RV decompensation in pulmonary arterial hypertension

Zhang, Y.; Bonnet, S.; Provencher, S.; Haromy, A. S.; Liu, Y.; Zhao, Y.-Y.; Breuils-Bonnet, S.; Bowles, D. E.; Mendiola Pla, M. A.; Sutendra, G.; Michelakis, E. D.

doi:10.1101/2025.07.25.666908

bioRxiv · 10.1101/2025.07.25.666908

A critical contribution of cardiac myofibroblasts in right ventricular failure and the role of UCP2 SNPs in the predisposition to RV decompensation in pulmonary arterial hypertension

Zhang, Y.·Bonnet, S.·Provencher, S.·Haromy, A. S.·Liu, Y.·Zhao, Y.-Y.·Breuils-Bonnet, S.·Bowles, D. E.·Mendiola Pla, M. A.·Sutendra, G.·Michelakis, E. D.

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Abstract

The mechanism of transition from compensated (cRV) to decompensated right ventricle (dRV) in pulmonary arterial hypertension (PAH) is unknown. We explored the role of RV cardiac myofibroblasts (cMFB) on this transition utilizing a rat model and 3 cohorts of 81 patients which included clinical data, RV tissues and blood. We hypothesized that the loss of UCP2, critical for mitochondrial calcium (mCa++) regulation and cardiac fibroblasts (cFB) differentiation, is associated with dRV in rats and humans; and that a loss-of-function UCP2 SNP (rs659366) may predict dRV in human PAH. We separated rat cRV from dRV based on catheterization and echocardiographic criteria and found a significant increase in cMFB in dRV. In isolated hearts, RV contractility was lower in dRV but not in isolated cardiomyocyte (CM), pointing to a non-CM cause. Mitochondrial respiration was lower in dRV cMFB than in control and cRV cFB. mCa++ was progressively decreased from normal to cRV to dRV c(M)FB, and the same was true for c(M)FB (but not CM) UCP2 levels. Human PAH, but not secondary pulmonary hypertension, dRVs had more cMFB and less UCP2 than control and cRVs. Decreased UCP2 (protein and mRNA) levels and the presence of heterozygous/homozygous UCP2 SNP were associated with worse RV performance (TAPSE, cardiac index), even among patients with similar mean pulmonary arterial pressure. Our data point to a change of cell identity (cFB to cMFB) in the RV as a driver of RV decompensation. UCP2 SNPs are promising biomarkers for early cRV transition to dRV in PAH.

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Zhang, Y., Bonnet, S., Provencher, S., Haromy, A. S., Liu, Y., Zhao, Y.-Y., Breuils-Bonnet, S., Bowles, D. E., Mendiola Pla, M. A., Sutendra, G., Michelakis, E. D.. 2025-07-29. A critical contribution of cardiac myofibroblasts in right ventricular failure and the role of UCP2 SNPs in the predisposition to RV decompensation in pulmonary arterial hypertension. https://doi.org/10.1101/2025.07.25.666908

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