Astronauts face many health challenges as a result of their time spent in the weightless environment of space. Cardiovascular remodeling (the process by which cells and tissues break down and build back up) in response to weightlessness predisposes space travelers to exercise intolerance and orthostatic intolerance (a physical state characterized by lightheadedness, palpitations and occasional fainting once they return to Earth). Dr. Shoukas’ research looks at these health challenges and tests the way that cardiovascular signaling molecules, such as nitric oxide, control the process of de-conditioning. He will be testing countermeasures to inhibit the de-conditioning process.
Overview
Non-Adrenergic Mechanisms of Cardiovascular Deconditioning
Principal Investigator:
Artin A. Shoukas, Ph.D.
Organization:
The Johns Hopkins University School of Medicine
Technical Summary
While our previous focus had remained on altered adrenergic signaling (from baroreceptor to adrenergic receptor) in the patho-physiology of orthostatic intolerance (OI), the potential role of nitric oxide (NO), a critical modulator of both cardiac and vascular function, became the focus of our investigation. In the vasculature, we have identified novel mechanisms by which NO regulates vascular endothelial function. We have also demonstrated that enhanced NO-dependent signaling (as a result of NOS phosphorylation) contributes to vascular contractile hyporesponsiveness, a central component of orthostasis. We are currently using in vivo techniques to noninvasively and serially measure vascular stiffness (as measured by pulse wave velocity) and to determine the contribution of altered arterial compliance to OI.
In addition, one of our graduate students, Mr. Eric Tuday, was selected as an NSBRI summer intern at the NASA Johnson Space Center in Drs. Janice Meck's and Steven Platt's Cardiovascular Laboratories. His collaborative studies with our group and Dr. Platt's group has proven to be very fruitful and we will be determining the changes in aortic and arterial compliances before, during and after long-term bed rest in human volunteers. These studies test the hypothesis that long-term bed rest increases arterial compliance which subsequently can decrease the cardiac output response during orthostatic challenges. With regard to the heart, we have determined for the first time that it is not loss of cardiac mass, but rather altered contractile function that contributes to OI. This depressed contractile function is likely the result of altered adrenergic signaling (of which we have identified a novel arm of the beta-l beta-2 AR signaling pathway) or altered NO signaling.
We have made significant contributions to the understanding of the intricate molecular mechanisms underlying the role of NO in the modulating cardiac contractile structure and function in general. We continue to determine the role of dysregulated NO in the pathobiology of OI. We now have a greater appreciation for the NO signaling dysregulation in OI and are uniquely poised to test the efficacy of the countermeasures aimed at regulating NO as laid out in our project.
We currently have a patent on the target site to inhibit Arginase II and are working with a venture capital group to further fund work to develop a specific designer drug which will inhibit Arginase II. The result of these negotiations has been very positive indeed. Red Abbey, a venture capital fund, is securing licensing through Acidophil, LLC. Acidophil, LLC is an intellectual property development company whose goal is to translate innovative life science technologies into products and businesses. Acidophils founders are Nobel Prize winner Sydney Brenner M.D., Ph.D., and Philip Goelet Ph.D. Licensing will be from both The Johns Hopkins University and the University of Pennsylvania both of which are necessary to take this technology into the marketplace. The new companys name will be Arginetix, Inc. This entire project has been translational and has the potential to advance novel targeted drugs to the clinical environment.
Earth Applications
These findings could have important therapeutic significance for both astronauts and long-term bed-rest patients. Both of these groups are predisposed to orthostatic intolerance, the former upon returning to normal gravity and the later when returning to the upright position, respectively. These findings could also have important therapeutic significance for the normal aging population.
In our animal models, we have used aortic atherosclerosis and plaque formation as the target endpoint, as this is an accessible site for the study of the vascular changes. Since it is accepted that dysfunctional endothelium is the root cause of initiating the atherosclerotic process, ArginaseII would promise to be a target for all sites of atherosclerosis.
In hypercholesteremia, supplementation of L-arginine improves endothelial-dependent relaxation and NO production. Arginase activity has also been shown to be increased in diabetes and hypertension induced by various cytokines and inflammatory stimuli. There is an emerging body of data that ArginaseII is up-regulated in the penis in humans with diabetes. Inhibition of Arginase has a significant enhancing effect on erectile function in aging and other disease processes in which NO signaling may be dysregulated, such as diabetes. Although it has not yet been tested it is likely that diabetes may be associated with an increase in endothelial Arginase activity. Furthermore, Arginase may well be a target for the treatment of diabetes-associated endothelial dysfunction. This can be easily tested in a diabetic mouse or rat model in the future.
The entire project has been translational and has the potential to advance novel targeted drugs to the clinical environment and to a broad spectrum of patients.
This project's funding ended in 2008