Hon, A. | Search bioRxiv

bioRxiv2025

The Liver is an Inflammatory Mediator of Pulmonary Arterial Hypertension

The livers contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30 - 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) [≥]12, predicting higher pulmonary vascular resistance ({beta}=0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na [≥]12 had decreased 6-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.

cell biology↗

bioRxiv2024

Effects of Exercise Frequency on Aortic Calcification in Hyperlipidemic Mice

Cardiovascular disease risk is associated with coronary artery calcification and is mitigated by regular exercise. However, the optimal regimen (activity level and frequency) for benefitting cardiovascular health is not clear. The surface area of calcium deposits, in addition to the quantity of calcium mineral, is a key factor in the risk of plaque rupture in humans due to compliance mismatch of edges with surrounding distensible tissue resulting in debonding. We previously found that aortic PET tracer uptake, a marker of mineral surface area, was reduced in hyperlipidemic (Apoe-/-) mice that underwent treadmill exercise, especially those in the low-speed (12.5 meters/min) regimen. To test the optimal exercise frequency on cardiovascular health, hyperlipidemic mice with baseline aortic calcification were subjected to none, 3- or 5-day/week treadmill regimen (12.5 meters/min for 30 min/day) for 5 weeks. MicroPET/microCT imaging and echocardiography were performed before and after the 5-week study. Results show that aortic calcification significantly progressed in all 3 groups, and 18F-NaF uptake increased in the control and 3-day groups, but not in the 5-day group. As for cardiac function, left ventricular (LV) systolic function was not affected but LV mass and wall thickness decreased in the 5-day group, suggesting cardiac remodeling. Skeletal bone density assessed at lumbar vertebrae shows that bone density decreased in all 3 groups. These findings suggest that, in mice with underlying calcific atherosclerosis, low-speed exercise and a frequency of 5 days/week is optimal for benefitting cardiovascular health.

physiology↗