VMI Researchers Uncover Molecular Origins of Pulmonary Hypertension to Help Speed Treatment

VMI investigators Elena Goncharova, PhD, and Stephen Chan, MD, PhD study how pulmonary hypertension develops in order to design better therapeutic interventions to prevent, regress, or cure this devastating cardiopulmonary disease. During the past year, both investigators have made remarkable discoveries in the molecular pathways that cause remodeling of pulmonary vascular tissue and limit blood flow between the heart and lungs. These discoveries will help identify drug targets that are likely to stop or significantly slow the disease progression.

Dr. Goncharova and her laboratory discovered a new mechanism that drives pathogenic proliferation and impairs apoptosis of vascular smooth muscle cells in small pulmonary arteries. They found that HIPPO, a key growth suppressor cassette that prevents organ overgrowth, is dysfunctional in small pulmonary arteries of patients with pulmonary arterial hypertension. This results in activation of transcriptional co-activators YAP and TAZ, unleash other pro-proliferative pro-survival signaling pathways and increases cell proliferation and survival. The researchers identified ILK1 as a key molecule that “locks” HIPPO in inactive state and showed that pharmacological inhibition of ILK1 restores HIPPO function and stops the cyclical process of molecular activations that causes dangerous cell proliferation and apoptosis resistance in pulmonary hypertension patients’ arteries. Selective ILK inhibitors can now be further explored as a promising strategy for therapeutic intervention to reverse pulmonary hypertension.

Dr. Chan and his laboratory discovered a novel link between pulmonary vessel wall stiffening and the way that these blood vessels create energy and biomass. Dr. Chan’s group found that this link is primarily controlled by the activation of YAP and TAZ which in turn control an enzyme called glutaminase. Activation of glutaminase sets in motion a metabolic process that ends in dangerous cell proliferation in the arteries of pulmonary hypertension patients. The Chan lab identified the YAP inhibitor verteporfin and the glutaminase inhibitor CB-839 as therapeutic drug candidates when used, either singly or together, can impede the molecular pathways driving this deadly disease.

PH Program Research Day for Patients – 2016

Once again, in celebration of Pulmonary Hypertension Month, the UPMC PH Program, in collaboration with PH researchers at the University of Pittsburgh’s Vascular Medicine Institute, hosted Research Day for Patients.

On November 22, 2016, PH patients and their guests were updated on the newest PH research innovations and discoveries, and clinical trials.  Scientists in the Vascular Medicine Institute were honored to welcome PH patients into their laboratories to get a behind-the-scenes tour of the facilities where our cutting-edge research happens.

Patient Julia Feitner’s story and Dr. Chan’s JCI paper highlighted in the Trib

Dr. Stephen Chan’s JCI publication was highighted in a recent Tribune-Review article featuring PH patient Julia Feitner:  “Experts seek origin of pulmonary hypertension to design treatment”.

Experts seek origin of pulmonary hypertension to design treatment

After she was diagnosed with pulmonary hypertension during a 2008 pregnancy, Julia Feitner feared she would have to make a choice between her baby's life and her own. The disease, which impedes passage of blood from the heart to the lungs, is especially hard on pregnant women, whose hearts need to pump extra blood to nourish their babies.

Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q, Zhao J, Tai Y, Tang Y, Zhang YY, Rehman S, Sugahara M, Qi Z, Gorcsan III J, Vargas SO, Saggar R, Saggar R, Wallace WD, Ross DJ, Haley KJ, Waxman AB, Parikh VN, De Marco T, Hsue PY, Morris A, Simon MA, Norris KA, Gaggiol, C, Loscalzo J, Fessel J, Chan SY (Senior Author). Vascular stiffness mechanoactivates YAP/TAZ- dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest. 2016. Sep 1;126(9):3313-35. [PMID 27548520 | PMCID PMC5004943].

UPMC earns PHA Accreditation as a Center for Comprehensive Care

The UPMC Comprehensive Pulmonary Hypertension Program has earned accreditation by the Pulmonary Hypertension Association (PHA) as a Center of Comprehensive Care.

 

Comprehensive Pulmonary Hypertension Program at UPMC Earns National Recognition - UPMC & Pitt Health Sciences News Blog

The Comprehensive Pulmonary Hypertension Program at UPMC has been added to the short list of programs nationwide to earn accreditation by the Pulmonary Hypertension Association (PHA) as a Center of Comprehensive Care. UPMC is one of 39 medical centers nationally to receive the distinction for the quality of its pulmonary hypertension program.