The typical cause of death in pulmonary hypertension (PH) is right ventricular (RV) failure, with females showing better survival rates than males. Recently, metabolic shift and mitochondrial dysfunction have been demonstrated in RV failure secondary to PH. In light of evidence showing that estrogen protects mitochondrial function and biogenesis in noncardiovascular systems, we hypothesized that the mechanism by which estrogen preserves RV function is via protection of mitochondrial content and oxidative capacity in PH. We used a well‐established model of PH (Sugen+Hypoxia) in ovariectomized female rats with/without estrogen treatment. RV functional measures were derived from pressure–volume relationships measured via RV catheterization in live rats. Citrate synthase activity, a marker of mitochondrial density, was measured in both RV and LV tissues. Respiratory capacity of mitochondria isolated from RV was measured using oxygraphy. We found that RV ventricular‐vascular coupling efficiency decreased in the placebo‐treated SuHx rats (0.78 ± 0.10 vs. 1.50 ± 0.13 in control, P < 0.05), whereas estrogen restored it. Mitochondrial density decreased in placebo‐treated SuHx rats (0.12 ± 0.01 vs. 0.15 ± 0.01 U citrate synthase/mg in control, P < 0.05), and estrogen attenuated the decrease. Mitochondrial quality and oxidative capacity tended to be lower in placebo‐treated SuHx rats only. The changes in mitochondrial biogenesis and function paralleled the expression levels of PGC‐1α in RV. Our results suggest that estrogen protects RV function by preserving mitochondrial content and oxidative capacity. This provides a mechanism by which estrogen provides protection in female PH patients and paves the way to develop estrogen and its targets as a novel RV‐specific therapy for PH.

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.

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Aims Cardiac fibroblasts (CF) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). β-arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that β-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. Methods and Results β-arrestin 1&2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and β-AR signaling is uncoupled with loss of β-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either β-arrestin 1 or 2 restored β-AR signaling and β-agonist mediated inhibition of collagen synthesis. Overexpression of β-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired β-AR signaling, and loss of β-agonist-mediated inhibition of collagen synthesis. β-arrestin knockdown in failing CF diminished TGF-β stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of β-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-β-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Conclusions Enhanced β-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of β-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of β-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.