MECHANISMS OF LEFT VENTRICULAR REMODELING IN PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Gabriel Grilo (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Cardiac remodeling is composed of molecular, cellular, and interstitial changes in the cardiac tissue that affect the size, shape, and function of the heart. There are two types of cardiac remodeling: physiological and pathological remodeling. Physiological remodeling of the heart is an adaptation of the organ based on the body"s demand, such as changes due to physical exercises and during aging. Cardiac pathological remodeling can occur due to the evolution of a chronic disorder in the cardiovascular system or after an acute injury, such as myocardial infarction (MI). In this thesis, we investigated both physiological and pathological cardiac remodeling, with particular focus on the role of the extracellular matrix (ECM). Determining the mechanisms involved in cardiac remodeling by changes in ECM provides insight to distinguish the local and functional changes from external risk factors; and it provides identification of novel targets that could be used as therapeutic approaches to reduce cardiac dysfunction. In our first study, we hypothesized that changes in ECM composition during physiological remodeling with age occurs in a sex-specific manner, since cardiac function varies between sexes among cardiovascular disease patients. We assessed cardiac parameters using both conventional echocardiography and speckle tracking echocardiography (STE). Our results suggest that STE allows for early detection of changes in cardiac function between sexes during aging. ECM factors involved in collagen metabolism, such as decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent; while periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex specific differences. These data highlight the importance of including sex-differences analysis when studying cardiac aging. In our second study, we investigated the role of a collagen-derived matricryptin in pathological remodeling. Matricryptins are biologically active peptides, generated from ECM proteolysis, able to regulate cell function and survival. We tested the potential of the matricryptin p1159 to reduce adverse cardiac remodeling using a rodent MI model. A previous study from our lab showed that p1159 plasma levels negatively correlate with left ventricle (LV) filling pressure, suggesting a beneficial role against adverse remodeling. In this thesis, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin alpha 4. Fibroblast migration is an essential step during cardiac healing. In addition, p1159 significantly improved cardiac function post-MI by inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Our data strongly supports matricryptin p1159 as a therapeutic treatment to reduce adverse remodeling post-MI.

Additional Information

Publication

Dissertation

Language: English

Date: 2020

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