The leading causes of chronic heart disease are all associated with a non-adaptive deposit of fibrous tissue in the heart. Since fibrous tissue interferes with both cardiac function and cardiac filling, it is a major cause of heart failure. Utilizing models of repetitive ischemia and angiotensin II infusion, this proposal intends to investigate the hypothesis that non-adaptive fibrosis of the heart arises from dysfunction of the immune and inflammatory mechanisms, which, under appropriate circumstances, are protective. The proposal studies the cell signaling associated with the uptake of specific inflammatory cells and the mechanisms by which this results in the generation of a specific fibroblast type that is obligate for cardiac fibrosis. We provide evidence that this mechanism is critical to non-adaptive cardiac fibrosis resulting from a variety of pathological causes. The goal of the project is to identify the common factors leading to cardiac fibrosis from diverse chronic cardiac conditions and suggest potential interventions which might mitigate this process.

Public Health Relevance

This project proposes to identify the signaling mechanisms associated with interstitial fibrosis of the heart common to multiple cardiac diseases utilizing repetitive ischemia and angiotensin II infusion models. The data suggests that immunoinflammatory dysregulation results in a Th2/M2 phenotypic response critical to the generation of myeloid-derived fibroblasts from M2 macrophages and interstitial fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089792-07
Application #
8589461
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2007-09-30
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Cieslik, Katarzyna A; Trial, JoAnn; Entman, Mark L (2017) Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast. J Mol Cell Cardiol 111:81-85
Suh, Ji Ho; Lai, Li; Nam, Deokhwa et al. (2017) Steroid receptor coactivator-2 (SRC-2) coordinates cardiomyocyte paracrine signaling to promote pressure overload-induced angiogenesis. J Biol Chem 292:21643-21652
Trial, JoAnn; Heredia, Celia Pena; Taffet, George E et al. (2017) Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis. Basic Res Cardiol 112:34
Crawford, Jeffrey R; Trial, JoAnn; Nambi, Vijay et al. (2016) Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein are Increased in Peripheral Artery Disease. J Cardiovasc Transl Res 9:184-93
Trial, JoAnn; Potempa, Lawrence A; Entman, Mark L (2016) The role of C-reactive protein in innate and acquired inflammation: new perspectives. Inflamm Cell Signal 3:
Mayr, Magdalena; Duerrschmid, Clemens; Medrano, Guillermo et al. (2016) TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function. Physiol Rep 4:
Medrano, Guillermo; Hermosillo-Rodriguez, Jesus; Pham, Thuy et al. (2016) Left Atrial Volume and Pulmonary Artery Diameter Are Noninvasive Measures of Age-Related Diastolic Dysfunction in Mice. J Gerontol A Biol Sci Med Sci 71:1141-50
Trial, JoAnn; Cieslik, Katarzyna A; Entman, Mark L (2016) Phosphocholine-containing ligands direct CRP induction of M2 macrophage polarization independent of T cell polarization: Implication for chronic inflammatory states. Immun Inflamm Dis 4:274-88
Trial, JoAnn; Entman, Mark L; Cieslik, Katarzyna A (2016) Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart. J Mol Cell Cardiol 91:28-34
Duerrschmid, Clemens; Trial, JoAnn; Wang, Yanlin et al. (2015) Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis. Circ Heart Fail 8:352-61

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