|
Vascular Medicine Branch (VMB)
Mark T. Gladwin, MD, Principal Investigator
The clinical research activities of the Vascular Medicine Branch are programmatically linked to the CC Critical Care Medicine Department. This collaborative program intends to develop a new scientific research program focused on four major lines of research, each containing a strong and smooth interaction between bench and bedside investigations.
These lines of research include:
- The molecular mechanisms of ischemia and reperfusion injury in the heart and other organs, focusing on the role of the mitochondria in this process,
- the role of nitrite as an intrinsic hypoxic signaling molecule and activity of hemoglobin and myoglobin as enzymatic nitrite reductases,
- mechanisms responsible for the gender difference in cardiovascular disease;
- mechanisms governing the development of pulmonary hypertension in the hemoglobinopathies and HIV infection, and
- mechanisms related to the atheroprotective properties of HDL
- Novel therapies targeting proliferative vasculopathy in pulmonary hypertension, atherosclerosis and sickle cell disease.
Dr. Mark Gladwin is currently Chief of the Vascular Medicine Branch, a new branch within the NHLBI. He 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 a one-year clinical fellowship in pulmonary medicine at the University of Washington in Seattle , he returned for a research fellowship at the Critical Care Medicine Department, CC, under the mentorship of James Shelhamer, Frederick Ognibene, Alan Schechter, and Richard Cannon.
Since 1998, Dr. Gladwin's research activities have led to four major scientific discoveries. These discoveries have resulted in 82 published peer-reviewed manuscripts, 15 pending or approved protocols, and more than 700 patient protocol enrollments at the NIH Clinical Center .
The four scientific discoveries include:
- The discovery that the nitrite anion is a circulating storage pool for NO bioactivity (Gladwin, et al. PNAS 2002).
- The discovery of a novel physiological function for hemoglobin as an electronically and allosterically regulated nitrite reductase (Cosby, et al. Nature Medicine 2003; Huang et al. JCI 2005). These studies reveal that nitrite is a potent vasodilator in humans, is bioactivated by reaction with deoxyhemoglobin to generate NO preferentially under hypoxic conditions and suggest that hemoglobin has an “enzymatic” property of a nitrite reductase that participates in hypoxic vasodilation. In related translational studies Dr. Gladwin has demonstrated that inhaled nitrite reverses hypoxic neonatal pulmonary hypertension in sheep (Hunter, et al. Nature Medicine 2004), and that infused nitrite solutions prevent post subarachnoid hemorrhage induced vasospasm in primates (Pluta et al. JAMA 2005) and prevent hepatic and cardiac ischemia-reperfusion injury and infarction in mice (Lefer et al. JCI 2005).
- The characterization of a novel mechanism of disease, hemolysis-associated endothelial dysfunction (Reiter, et al. Nature 2003; Morris et al. JAMA 2005; Minneci et al. JCI 2005 in press). This work has described a state of resistance to NO in patients with sickle cell disease caused by scavenging of nitric oxide by hemoglobin, released into plasma during hemolysis.
- The mechanistic, clinical, and epidemiological description of a human disease syndrome, hemolysis-associated pulmonary hypertension (Gladwin, et al. NEJM 2004). He has found that pulmonary hypertension occurs in 30% of patients with sickle cell disease, is a major cause of mortality in this population (odds ratio 10:1), and is strongly associated with high hemolytic rate, iron overload and kidney disease.
|
