Cellular Plasticity in the Diabetic Myocardium
Abstract
The incidence of diabetes has been steadily increasing worldwide. Treating patients with diabetes presents unique challenges because diabetes has a negative impact on the function of many different organs. Particularly damaging are complications related to the function of the heart that eventually lead to heart failure. We now know that worsening heart function in diabetics is mainly due to (a) excessive production and deposition of collagen fibers between myocytes that make scars and stiffen the heart muscle and (b) gradual loss of blood vessels that reduces supply of nutrients and oxygen to the high energy demand heart tissue. The cellular changes and molecular signals that cause an increase in fibrosis or scarring and a decline in capillary density in the diabetic heart remain mostly unknown. Our published studies show that diabetes causes a marked increase in the expression of a large protein called thrombospondin (TSP)-1. TSP-1 is deposited in heart tissue and has been linked to both high collagen production, causing fibrosis, and to loss of capillaries. How high TSP-1 exerts these negative effects is not understood. We hypothesize that abnormal TSP-1 deposition in the diabetic heart has multiple effects that together cause heart tissue damage. First, TSP-1 directly activates collagen production in fibroblasts increasing scarring in heart tissue. Second, TSP-1 causes death of endothelial cells and their supporting cells or pericytes, compromising the survival of blood vessels. Third, TSP-1 alters the fate of highly plastic cells, turning blood vessels to scar. The structure of TSP-1 has been carefully studied and divided in several distinct functional domains. We will systematically evaluate the activity of each domain and its ability to selectively cause any of the defects found in diabetic hearts using small peptides that target the activity of specific TSP-1 domains. Because small peptides are easily synthesized and delivered, our work may quickly lead to new strategies to prevent fibrosis and promote blood vessel formation in diabetic patients, restoring heart function. As diabetes-associated dysfunction in other organs such as the kidney and eye has also been linked to fibrosis and capillary loss, our results may have broader implications in understanding and treating diabetic complications. Our proposal is directly related to two of the Fiscal Year 2015 Peer Reviewed Medical Research Program topic areas: "Cardiovascular Health" and "Diabetes" and aims to generate new information of outstanding significance for understanding the pathophysiology of diabetes-associated fibrosis, capillary loss and cardiac dysfunction. As the incidence of diabetes has reached epidemic proportions, the results of the proposed research project may have a significant impact on preventing diabetes-associated organ failure in military families and the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610622
Entities
People
- Antonis Hatzopoulos
Organizations
- United States Army
- Vanderbilt University