Many of us associate “nitrates” with the preservatives in bacon that can give you stomach cancer. But did you know that bacteria in your mouth can transform nitrites into nitrates which can then turn into nitric oxide (NO)? And that NO is a natural signaling path contributing to essential physiological functions like regulating blood pressure? Join us on April 15, 2016 as Dr. Mark T. Gladwin, Director of the newly formed Hemostasis and Vascular Biology Research Institute and Chair of the Department of Medicine at the University of Pittsburgh School of Medicine, presents some of his recent findings on therapeutic applications of NO in this year’s Joseph V Scaletti Catalyst Lecture:

Translating Redox Biology to Medicine

Nitrite as a hypoxic signaling molecule and new therapy for pulmonary hypertension

Nitrate and nitrite have traditionally been considered dietary toxins that increase the risk of stomach cancer. Recent scientific discoveries suggest that nitrate and nitrite are in fact natural signaling pathways in the human body, via a NO synthase independent reductive pathway from nitrate-to-nitrite-to-NO. Nitrite is now appreciated as a biological reservoir of nitric oxide (NO), present in plasma, red cells and organ systems, that is reduced to NO during physiological and pathological hypoxia. Current studies by multiple research groups indicate that nitrite forms via reduction of dietary nitrate to nitrite by commensal mouth bacteria, in addition to NOS-dependent nitrite formation from NO oxidation. Nitrite then contributes to critical physiological functions such as blood pressure control, hypoxic vasodilation, mitochondrial respiration and the cellular resilience to ischemic stress. Pre-clinical and clinical studies suggest that inhaled and oral nitrite may be able to prevent and reverse established pulmonary arterial hypertension and phase II proof of concept trials are currently in progress in the US and Europe. It is proposed that the nitrate – nitrite – NO pathway represents a fundamentally conserved pathway for physiological and pathological hypoxic NO-signaling in biology.

Dr. Gladwin has published over 320 manuscripts since 1996, which have had a significant impact on the fields of vascular and nitric oxide biology. His work is cited more than 3,700 times per year with an h-index of 85. Among his major scientific discoveries is the finding that the nitrite salt is a biological signaling molecule that regulates physiological and pathological hypoxic responses, blood pressure and flow, and dynamic mitochondrial electron transport. He characterized the role of hemoglobin and myoglobin as signaling nitrite reductases that regulate NO production under hypoxia. His seminal publication on this topic in 2003 has been cited more than 1150 times and is listed by Nature Medicine in its top ten Classic Collection. This work has led to the development and licensing of intravenous, oral and inhaled nitrite as a human therapeutic, with completion of animal toxicology, GMP formulations and phase Ia and Ib clinical trials. Phase II trials of inhaled nitrite are now underway for the treatment of pulmonary arterial hypertension, metabolic syndrome, and heart failure with preserved ejection fraction. In addition to studies of nitrite, he characterized a novel mechanism of disease, hemolysis-associated endothelial dysfunction. This work has described a state of resistance to NO in patients with sickle cell disease, malaria, transfusion of aged blood, and other hemolytic conditions, caused by scavenging of nitric oxide by hemoglobin that is released into plasma during hemolysis. These studies translated to clinical and epidemiological descriptions of a human disease syndrome, hemolysis-associted pulmonary hypertension. These investigations form the backbone of Dr. Gladwin’s current work at the University of Pittsburgh’s Hemostasis and Vascular Biology Research Institute and the Division of Pulmonary, Allergy and Critical Care Medicine.

Mark Gladwin received his M.D. from the University of Miami Honors Program in Medical Education in 1991. After completing his internship and chief residency at the Oregon Health Sciences University in Portland, Ore., he joined the NIH in 1995 as a critical care fellow in the Clinical Center. After completion of a clinical fellowship in pulmonary medicine at the University of Washington in Seattle, he returned for a research fellowship at the Critical Care Medicine Department under the mentorship of James Shelhamer, Frederick Ognibene, Alan Schechter, and Richard Cannon. He later served as the Chief of the Pulmonary and Vascular Medicine Branch within the NHLBI, NIH. In August of 2008, Dr. Gladwin became Chief of the Pulmonary, Allergy and Critical Care Medicine Division at the University of Pittsburgh School of Medicine and the Director of the newly formed Hemostasis and Vascular Biology Research Institute (now the Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute). In March 2015, Dr. Gladwin was appointed Chairman of the Department of Medicine in the University of Pittsburgh School of Medicine.

Each year, the Joseph V. Scaletti Catalyst Lecture series features scientific breakthroughs by a biomedical researcher at the forefront of the transition from lab bench and classroom to the bed side, contributing to more healthy and productive lives.

Friday, April 15, 2016