The Role of Transglutaminase-2 (TG2) in Ischemic and Non-Ischemic Heart Failure
Abstract
In addition to cardiomyocytes (the cardiac cells responsible for heart contraction), the heart contains abundant fibroblasts (cells that synthesize extracellular matrix and provide structural framework for tissues) and a significant number of macrophages (a type of white blood cells that engulfs and digests cellular debris, microbes, etc.). Fibroblasts can be activated following injury and deposit extracellular matrix proteins in an attempt to repair the heart. In heart failure, excessive activation of cardiac fibroblasts results in deposition of large amounts of extracellular matrix, increasing the stiffness of the heart. A stiff heart fails to relax properly; as a result, pressures in the cardiac chambers increase and patients develop shortness of breath. Moreover, deposition of matrix in the heart may precipitate deadly heart rhythm irregularities. Cardiac macrophages on the other hand are also activated following injury and clear the injured cells. Again, inappropriate activation of macrophages may accentuate injury, increasing cardiomyocyte death and extending fibrosis. The molecules that cause perturbations in cardiomyocytes, fibroblasts, and macrophages, leading to heart failure are very poorly understood. Our laboratory has identified the protein transglutaminase-2 (TG2, also known as tissue transglutaminase) as an important mediator in heart failure. TG2 expression is highly increased in failing hearts. TG2 is expressed by all cardiac cell types and is also deposited in the extracellular matrix. TG2 can act both as an enzyme (catalyzing protein crosslinking) and as an adapter/scaffold protein with non-enzymatic signaling effects. Inhibition of TG2 may reduce fibrosis of the heart by decreasing crosslinking of the cardiac matrix. However, development of new therapies targeting TG2 requires understanding of its effects on different cell types. Our proposed studies will examine the effects of TG2 in the two most common situations associated with heart failure: myocardial infarction and pressure overload. We will use mice engineered to lack TG2 specifically in cardiomyocytes, fibroblasts, or macrophages to study the effects of the protein in these cell types. We will also perform cell culture experiments to investigate the role of TG2 in regulating the responses of these cells. We will use several different small molecule inhibitors of TG2 to identify the ones with the most favorable profile and we will perform TG2 inhibition experiments in mice undergoing infarction protocols. Our ultimate goal is to implement TG2 inhibition as a new strategy for treatment in heart failure. However, this requires careful dissection of the effects of TG2 on each cell type and understanding of the relative significance of enzymatic and non-enzymatic function of the molecule. The proposed concepts will be studied in four specific aims: Specific Aim 1 will investigate the effects of TG2 on cardiomyocytes in myocardial infarction and in the cardiomyopathy associated with left ventricular pressure overload. Specific Aim 2 will study the effects of TG2 on macrophage phenotype and function in ischemic and non-ischemic heart failure. Specific Aim 3 will explore the role of TG2 in regulating fibroblast activation in infarcted and remodeling hearts. Specific Aim 4 will dissect the relative role of enzymatic and non-enzymatic actions of TG2 in the failing heart. We anticipate that our studies will provide new information on the pathogenesis of ischemic and non-ischemic forms of heart failure and may identify TG2 inhibition as a new and effective therapy. The availability of TG2 inhibitors, which are currently tested in humans, makes this therapeutic direction particularly attractive.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910283
Entities
People
- Nikolaos G Frangogiannis
Organizations
- Albert Einstein College of Medicine
- United States Army