Right ventricular load and contractility in HIV-associated pulmonary hypertension.

BackgroundPeople living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH.MethodsWe performed a retrospective review of patients with a diagnosis of HIV undergoing right heart catheterization (RHC) from 2000-2016 in a tertiary care center. Inclusion criteria were diagnosis of HIV, age ≥ 18 years and availability of RHC data. PH was classified as either pulmonary arterial hypertension (PAH; mean pulmonary arterial pressure [mPAP] ≥ 25mmHg with pulmonary artery wedge pressure [PAWP] ≤ 15mmHg) or pulmonary venous hypertension (PVH; mPAP ≥ 25mmHg with PAWP > 15). We collected demographics, CD4 cell count, HIV viral load, RHC and echocardiographic data. The single beat method was used to calculate RV-PA coupling from RHC.ResultsSixty-two PLWH with a clinical likelihood for PH underwent RHC. Thirty-two (52%) met PH criteria (15 with PAH, 17 with PVH). Average time from diagnosis of HIV to diagnosis of PH was 11 years. Eleven of 15 individuals with PAH were on antiretroviral therapy (ART) while all 17 patients with PVH were on ART. Compared to PLWH without PH, those with PH had an increased likelihood of having a detectable HIV viral load and lower CD4 cell counts. PLWH with PAH or PVH had increased RV afterload with normal RV contractility, and preserved RV-PA coupling.ConclusionPLWH with PH (PAH or PVH) were more likely to have a detectable HIV viral load and lower CD4 count at the time of RHC. PLWH with PAH or PVH had increased RV afterload, normal RV contractility, with preserved RV-PA coupling suggestive of an early onset, mild, and compensated form of PH. These results should be confirmed in larger studies

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension.

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.le Canceropole PACA; la Region PACA; le Conseil Departementale 06; I'INSERM; ARC; IBiSA; Conseil Departemental 06 de la Region PACA; NIH [HL096834, HL124021, P01-HL103455, R56-HL126525, R01-HL090339, HL61795, HL48743, HL108630, GM107618, HL007633, HL128802, HL121174]; American Heart Association; Ligue Nationale contre le Cancer; Fondation Bettencourt-Schueller; French National Research Agency [ANR-11-LABX-0028-01]; Association pour la Recherche sur le Cancer (ARC) [PJA20131200325]; Gilead Sciences, Inc.Authors retain rights to present the work without prior permission in original, revised, adapted, or derivative form, provided that all such use is for personal or nonprofit (and noncommercial) benefit, is consistent with any employment agreement, and references the original publication citation. Examples: reproduction in nonprofit publications; lecture display (slides, overheads, or digitized media); hosting on personal or curriculum vitae-oriented websites; and inclusion in institutional and/or funding-body repositories.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]