tPPG | Vascular Medicine Institute

tPPG: Vascular Sub-Phenotypes of Lung Disease

Research

With the support of a five-year translational program project grant (tPPG) from the National Institutes of Health, a team of researchers from the Vascular Medicine Institute has undertaken a series of studies to define the common mechanistic and therapeutic pathways of pulmonary hypertension in the context of major lung and systemic diseases, such as the metabolic syndrome, and target this biology with new drug strategies. Based on extensive data generated over the last five years, these researchers propose that new nitrate-nitrite-nitric oxide-nitro-fatty acid therapies could target both the metabolic syndrome and the pulmonary vasculature, and will limit disease progression in patients with both pulmonary hypertension and metabolic syndrome.

The tPPG is composed of three projects, each with a component of basic science as well as a trial of a promising new drug therapy. Project 1, led by Mark Gladwin, MD, focuses on nitrite therapy for patients with pulmonary hypertension coupled with heart failure with preserved ejection fraction. Project 2, led by Bruce Freeman, PhD, focuses on electrophilic nitro-fatty acid therapy for sufferers of pulmonary arterial hypertension. Project 3, led by Alison Morris, MD, MS, focuses on the contributions of the microbiome to the reduction of nitrate to nitrite, and the downstream products of this in vivo metabolism to nitric oxide and fatty acid nitration products.

Project 1: Exploring the Effects of Oral Nitrite Therapy on Exercise Capacity, Hemodynamics, and Insulin Resistance in Subjects with PH-HFpEF

Dr. Gladwin’s project explores the hypothesis that new vascular-targeted, nitric oxide-based therapeutic strategies will enhance the treatment of pulmonary arterial hypertension and metabolic syndrome, providing a new therapy for the currently untreatable and extremely common pulmonary hypertension in the setting of heart failure with preserved ejection fraction (PH-HFpEF). To this end, Dr. Gladwin’s team has identified two reactive nitrogen species that potently modulate both pulmonary hypertension and the metabolic syndrome, nitrite (NO2-) and nitro-fatty acids (NO2-FA).

Mark Gladwin, MD

Principal Investigator

Charlie McTiernan, PhD

Frank Sciurba, MD

Jesus Tejero, PhD

Project 2: Establishing the Safety and Efficacy of OA-NO2 Therapy in Subjects with Pulmonary Arterial Hypertension and Metabolic Syndrome

Dr. Freeman’s team hypothesizes that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. The overarching goal is to characterize and deploy a product of nitrate-nitrite-nitric oxide metabolism, electrophilic nitro-fatty acids (NO2-FA), as a new therapeutic strategy for pulmonary arterial hypertension. Researchers will unravel the roles of fatty acids in transducing nitrogen oxide signaling by studying the responses of candidate NO2-FA-regulated enzymes and key transcriptional regulatory protein targets.

Bruce Freeman, PhD

Principal Investigator

Nicholas Khoo, PhD

Patrick Pagano, PhD

Stacy Wendell, PhD

Steven Woodcock, PhD

Project 3: Exploring the Genetic, Microbiome, and Environmental Determinants of Pulmonary Hypertension

The goal of this project is to define the relationships between pulmonary hypertension, high fat diet, the oral and gut microbiome, and the metabolism of nitrogen oxide signaling mediators that may regulate the development, severity, and treatment of pulmonary hypertension. Dr. Morris’s team hypothesizes that the commensal microbiome can be beneficial in pulmonary hypertension because of its function in bioactivation of the nitrate-nitrite-nitric oxide-nitro-fatty acid pathway.

Alison Morris, MD, MS

Principal Investigator

Imad al Ghouleh, PhD

Takis Benos, PhD

Meghan Fitzpatrick, MD

Carl Koch, MD

Barbara Methé, PhD

Chris O'Donnell, PhD

Michael Risbano, MD, MA

The goals of this tPPG-funded collaboration are supported by a pre-clinical assessment core; a bioanalytical core, led by Sruti Shiva, PhD; a clinical core; and an administrative core, led by Mark Gladwin, MD.

Publications

Al Ghouleh I, Meijles DN, Mutchler S, Zhang Q, Sahoo S, Gorelova A, Henrich Amaral J, Rodriguez AI, Mamonova T, Song GJ, Bisello A, Friedman PA, Cifuentes-Pagano, ME, Pagano PJ. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci USA. 113(36):E5308-17. [PMID 27540115 | PMCID PMC5018796]

Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J 3rd, Parsley EL, Gladwin MT. (2016) Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 1(18):e89620. [PMID 27812547 | PMCID PMC5085611]

Sahoo S, Meijles DN, Al Ghouleh I, Tandon M, Cifuentes-Pagano ME, Sembrat J, Rojas M, Goncharova EA, Pagano PJ. (2016) MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension. PLoS One. 11(5):e0153780. [PMID 27144530 | PMCID PMC4856285]

Koch CD, Gladwin MT, Freeman BA, Lundberg JO, Weitzberg E, Morris A. (2016) Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med. pii: S0891-5849(16)31102-9. [PMID 27989792]