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.

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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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Adhikari, Bishow B
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Wang, Yuguo; Jia, Li; Hu, Zhaoyong et al. (2018) AMP-activated protein kinase/myocardin-related transcription factor-A signaling regulates fibroblast activation and renal fibrosis. Kidney Int 93:81-94
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
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
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
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:
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
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:
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; 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

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