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The increased afterload of pulmonary arterial hypertension (PAH) impairs right ventricular function, as the RV struggles to adapt to increased pressure with remodeling and fibrosis. RV failure is the primary cause of death in PAH, and a frequent cause of death in pulmonary hypertension secondary to pulmonary embolism, emphysema, pulmonary fibrosis, and left-heart failure. There is currently no RV-specific therapeutic to maintain function and prolong patient life. During PAH, cardiomyocytes upregulate cell-surface expression of the G αq /IP 3 -coupled thromboxane/prostanoid receptor (TPr), which is activated by multiple endogenous ligands increased in PAH, and leads to calcium influx. TPr activation is also pro-fibrotic in multiple cell types and models. Previous studies have shown reduced fibrosis following TPr antagonism in mouse models of short-term pulmonary hypertension; however this effect has been variable in long-term studies. To more precisely determine the functional effects of TPr activation in RV pressure overload, we used pulmonary arterial banding (PAB) for a direct, sustained increase in pressure, antagonism or deletion of the TPr, and murine cardiac MRI for simultaneous evaluation of the RV and LV. TPr antagonism in a long-term PAB model improved RV ejection fraction and restored LV volume and output by preventing septal bulging and LV eccentricity. This occurred with even short-term antagonism, and was associated with decreased fibrosis in the septum and RV insertion points. Similar results were seen following PAB of universal or cardiomyocyte-specific TPr knockout mice; in all cases, decreasing TPr activation during RV pressure overload reduced RV stiffness even when RV fibrosis remained unchanged. In long-term pressure overload, the improved compliance with antagonism normalized expression of Yap/Taz-associated genes. These results suggest that TPr activation contributes to cardiomyocyte mechanotransduction and deleterious remodeling in response to the RV pressure overload of pulmonary hypertension, and that antagonism of the TPr may preserve RV function to prolong life in PAH patients.

Background: Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. Facets of PH have been characterized in isolation, but many have yet to be unified by a common upstream regulator. Methods & Results: We constructed a network in silico of 247 genes and 2,274 functional interactions involved in PH. Using this model and advanced network analysis, we predicted the miR-130/301 family to have the most diverse pool of PH-relevant target genes among conserved microRNAs (miRNAs). Guided by these predictions, we found that this family was up-regulated by hypoxia, inflammatory cytokines, and factors genetically linked to PH. MiR-130/301 family members were also up-regulated in remodeled pulmonary vessels in 7 animal models and 3 human subtypes of PH. Via gain- and loss-of-function experiments in vitro , we found that miR-130/301 suppressed a cohort of PPARgamma-related targets to regulate two pro-proliferative pathways (the apelin-miR-424/503-FGF2 axis in PAECs and the STAT3-miR-204-SRC axis in PASMCs); vasomotor tone ( e.g. , endothelin-1 and endothelial nitric oxide synthase); and extracellular matrix remodeling ( e.g. , the collagen crosslinking enzyme LOX). In turn, delivery of miR-130a mimic oligonucleotides in pulmonary vessels of mice altered expression of the predicted cohort of PPARgamma-related factors, leading to increased vascular remodeling (19.62±1.36 percent muscularized arterioles for miR-130a vs. 6.98±0.55 percent for scrambled control, p3 *dyn*s*cm -5 ] for miR-130a vs. 462±25.4 for control, pin vivo via antisense oligonucleotides mitigated these effects. Conclusions: We used network modeling to identify miR-130/301 as a master regulator of PH and a novel potential therapeutic target. These findings provide critical support for the evolving application of network modeling to discover the hidden molecular origins of PH and other human diseases.