Sex hormone signaling in pulmonary hypertension (PH) and right ventricular (RV) failure
We have a major interest in identifying modifiers and targets of sex hormone signaling in the cardiopulmonary system. We described for the first time that 17β-estradiol (E2) attenuates hypoxic pulmonary vasoconstriction in isolated pulmonary artery rings in an estrogen receptor (ER)-, endothelium- and nitric oxide (NO)-dependent fashion. We extended these observations to an in vivo model of hypoxia-induced PH and discovered for the first time that E2 exerts specific anti-proliferative effects on pulmonary artery endothelial cells (PAECs) during hypoxia, but not during normoxia. We subsequently identified an ER-specific genome in the lungs of chronically hypoxic PH rats and identified the BMPR2 antagonist gremlin 1 as a novel target of the ER in the pulmonary vasculature. Further mechanistic studies discovered a novel mechanism where hypoxia, in a HIF-1α dependent manner, up-regulates ERβ in PAECs, which in turn activates the HIF inhibitor prolyl hydroxylase 2 and attenuates HIF-1α & HIF-2α activation. We discovered that E2 exerts ER-mediated protective effects on RV function that include beneficial effects on pro-contractile and pro-angiogenic signaling as well as inhibitory effects on pro-apoptotic and pro-inflammatory signaling. We identified a novel signaling axis in which E2, through ERα, increases BMPR2 and apelin in RV cardiomyocytes to exert cardioprotective effects. We recently extended our studies to human PAH patients, where we showed for the first time that female patients exhibit better RV-pulmonary vascular coupling than male patients. We are currently studying additional pathways and targets employed by E2 and ERα in the RV, such as angiogenesis, inflammation and metabolic function.
In collaboration with Drs. Ben Gaston (Indiana University) and Dawn Newcomb (Vanderbilt University) and under the umbrella of an NHLBI-funded PPG, we are studying the role and downstream targets of the androgen receptor in airway epithelial cells from patients with severe asthma. This project also entails a clinical trial of dehydroepiandrosterone (DHEA) for patients with severe asthma and underlying genetic alterations in androgen metabolism.
In collaboration with Dr. Beth Brown (University of Washington), we are studying mechanisms of protective effects of exercise in PH. We demonstrated for the first time that an individualized exercise regimen is associated with pulmonary artery pressure-lowering effects, NO release, and lack of detrimental effects on RV function. In additional studies, we demonstrated that female rats exhibit superior RV adaptation to acute strenuous exercise, and that these effects are mediated by protective effects of 17β-estradiol on pro-apoptotic signaling, endothelial NO production and autophagic flux. Lastly, we demonstrated that high intensity interval training is superior to customary continuous exercise training for improving hemodynamics and maladaptive RV hypertrophy in a rodent model of PAH. We recently expanded our studies to PAH patients and demonstrated safety and efficacy of a home-based exercise program. Ongoing studies focus on identifying effects of specific exercise and nutrition interventions on PH and RV function endpoints.
In order to identify whether bronchopulmonary dysplasia (BPD) represents a risk factor for PH development later in life, we extended our interest in hypoxia exposure to individuals with a history of BPD. With Dr. Kara Goss (then a postdoctoral fellow in my laboratory; now UT Southwestern) and Dr. Robert Tepper (Indiana University), we discovered that rats with postnatal hyperoxia exposure and a BPD phenotype develop more severe PH upon hypoxia exposure in adulthood. However, despite the more severe PH in these animals, their phenotype is characterized by better RV function, indicating that postnatal hyperoxia allows for a more adapted RV upon PH development later in life. In a follow-up investigation, we identified that previously hyperoxic animals are able to increase their cardiac output when their diffusing capacity decreases, while animals without prior hyperoxia exposure are not able to mount such a response. We identified that the RV in PH animals with a prior history of postnatal hyperoxia exposure is characterized by a more profound switch to a fetal phenotype, thus allowing for better adaptation to the increase in RV afterload. We recently translated these findings to the clinic, where we identified premature birth and respiratory disease early in life as risk factors for the development of adult PH. We have now expanded our studies to study effects of perinatal hypoxia on the cardiopulmonary transcriptome during lung development and identified potential novel mediators of lung and RV adaptation to chronic hypoxia. Ongoing studies focus on effects of ERα on cardiopulmonary function during perinatal hypoxia.
As a physician in the VA system, Dr. Lahm has a strong interest in identifying unique PH phenotypes in veterans. With collaborators Drs. Maron, Choudhary, Zamanian and Leary, we harnessed the Veterans Affairs Clinical Assessment Reporting & Tracking (CART) cohort to identify novel PH phenotypes and to decipher pharmaco-epidemiological patterns in the VA system. We showed in the largest cohort to date (n=21,727) that even mild elevations of PA pressures that do not yet qualify as PH are associated with increased morbidity and mortality. Furthermore, we identified that female veterans with PH exhibit more favorable hemodynamics and lower mortality than men. We also showed that histamine receptor 2 blockers use is associated with lower mortality in veterans with PH. Lastly, we discovered that ACE inhibitor or angiotensin receptor blocker use associates with lower mortality in veterans with PH.
The Lahm lab has a strong interest in translational and clinical questions pertaining to RV function and hemodynamic aspects of PH. We published the first report of RV contractile and diastolic dysfunction in RVs from rats with sugen/hypoxia-induced PH using the Langendorff (isolated heart) model. In collaboration with Dr. Jeff Kline, we performed a multicenter randomized controlled trial evaluating effects of inhaled nitric oxide on RV function in patients with intermediate risk pulmonary embolism. His expertise in the study of RV function allowed Dr. Lahm to lead an ATS Working Group of 20 content experts that identified knowledge gaps and pathways for progress in RV failure research. Lastly, in collaboration with members of the NIH PAH biobank, we contributed to several reports that identified novel genetic variations in PAH.
Research in the Lahm lab is funded through NIH 1R01HL144727 - 01A1, NIH 1P01HL158507, and VA Merit Review Award 2 I01 BX002042.