Basic and Translational Research:
My laboratory has been studying the mechanisms contributing to the pathobiology of vascular dysfunction in diseases such as age related systolic hypertension, atherosclerosis, radiation and pulmonary hypertension for the last 17 years. This integrated vascular biology laboratory has been continuously funded for 13 years by the NIH, as well as the American Heart Association and NASA through the National Space Biomedical Research Institute. Our vascular research program has attracted undergraduates, from the Johns Hopkins Homewood campus as a result of my joint appointment in the Dept. of Biomedical Engineering. We have also been fortunate to attract and train both Masters and PhD students. and train both MD and PhD Post-doctoral fellows, from the Departments of Anesthesiology, Cardiology and Pulmonary Medicine at Hopkins, and from around the country and the world. Many of the graduate and post-doctoral fellows have received funding through foundations such as the AHA and the Foundation for Anesthesia Education and Research (FAER). The majority of mentees have gone on to productive and successful careers in academic medicine, basic and translational science, and industry. It is our goal to continue to train the best academicians in cardiovascular biology such that this next generation of clinician and basic scientists will be able to address the medical needs and challenges of the rising cardiovascular burden. Our major contributions to science include 1) Arginase 1 and its contribution to age-related endothelial dysfunction and vascular stiffness. We were the first to demonstrate that arginase in endothelial cells reciprocally regulates nitric oxide production leading to eNOS uncoupling and endothelial dysfunction and vascular disease. This has led to the emergence of a robust literature on arginase upregulation and vascular disease. It has also led to the development of small molecule inhibitors of arginase for therapy of diseases in which endothelial dysfunction is a significant component. 2) Arginase 2 as a novel target in atherosclerosis: As with age-related endothelial dysfunction we described the mechanisms by which upregulation of arginase 2 by atherogenic stimuli such a as OxLDL through the Lox-1 receptor contributes to atherosclerosis. 3) Radiation induced vascular dysfunction: With funding from NASA and the National Space Biomedical Research Institution (through NASA) to explore the role of Galactic cosmic radiation in the context of space flight beyond low earth orbit, we explored the mechanisms of radiation induced endothelial injury and potential countermeasures to attenuate it. Using both conventional gamma radiation and high linear energy transfer radiation (using the NASA Research laboratory beamline at Brookhaven National Labs, Long Island) we determined the importance of Xanthine oxidase as a producer of radiation -induced oxidative stress and dysfunction in the endothelium. 4) Role of tissue transglutaminase (TG2) and other cross-linking matrix enzymes in Age-related vascular stiffness: Vascular stiffness and resultant age-dependent systolic hypertension remains an independent risk factor in cardiovascular disease. The molecular mechanisms underlying vascular stiffness remain incompletely understood. We have identified impaired nitric oxide bioavailability as an important contributor to vascular stiffness. Nitric oxide not only regulates vascular function through alterations in vascular tone but modifies the function of enzymes and other proteins by redox-dependent modification, S-nitrosylation. We have demonstrated that impaired NO bioavailability enhance the activity of the cross-linking enzyme tissue transglutaminase (TG2) which in turn contributes to increases in vascular stiffness. Using a secretome proteomic approach we have identified other enzymes that might contribute to age-related vascular stiffness: 5) Role of Opsins in the regulation of photorelaxation and vascular function: Classic sensory receptors in extrasensory sites and their roles in signal transduction: In a serendipitous finding we have discovered a light activated non-visual opsin, melanopsin (opsin 4 (Opn4))-dependent vasorelaxant pathway which in the presence of a beta adrenergic receptor kinase 1 (ARK 1 or GRK2) inhibitor is profoundly amplified. We have thus characterized an endogenous opsin-mediated, light-activated molecular switch for vasorelaxation that can be targeted for therapy in all diseases in which altered vasoreactivity is a significant pathophysiologic contributor.
All of these contribution have been or are funded by independent R01’s except for the radiation work which was funded by NASA and the National Space Biomedical Research Institution.
Clinical Research:
1) Age-related vascular stiffness and outcomes: As we age, our large conduit vessels (aorta) become stiffer, a process that leads to systolic hypertension. This vascular stiffness is and independent predictor of MACE. While this has been show in the context of patients following MI, stroke and renal dysfunction, the role of vascular stiffness as a predictor of peri-operative outcome has not been explored. Moreover, while chronologic age is immutable, vascular age is modifiable. Using newly developed devices and technique we continue to study the role of vascular stiffness in peri-operative outcomes and explore interventions that might improve vascular “age” and thus peri-operative outcomes.
2) Red cell health and transfusion: While transfusion is associated with adverse outcomes, the mechanisms underpinning is incompletely understood. Using multiple measures of erythrocyte health including RBC deformability, oxidative stress, NO we continue to explore the effect of storage duration on these metrics.
