Date of Award

2019

Embargo Period

1-1-2019

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Medicine

College

College of Graduate Studies

First Advisor

Amy D. Bradshaw

Second Advisor

Robin Muise-Helmericks

Third Advisor

Jeffrey Jones

Fourth Advisor

Kristine Deleon-Pennell

Abstract

Heart failure is one of the leading causes of death in the United States. Heart failure with preserved ejection fraction (HFpEF) is commonly associated with individuals with hypertension. Increases in myocardial hemodynamic load are recapitulated in murine models of pressure overload (PO) induced by trans-aortic constriction (TAC). In both human and TAC hearts, increases in fibrosis are demonstrated and align with increases in myocardial stiffness, a hallmark of diastolic dysfunction in HFpEF. Previous studies indicated that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) was essential for the development of cardiac fibrosis in TAC hearts, however the mechanisms behind the functional significance of SPARC in cardiac fibrosis has yet to be defined. This study utilizes a bone marrow transfer model to determine the role of SPARC expression in bone-marrow derived cells during the onset of cardiac fibrosis induced by TAC. Following induction of PO by TAC, SPARC-null mice transplanted with WT bone marrow demonstrated levels of fibrosis similar to that of wild type hearts despite the abrogation of SPARC expression by resident cardiac cells. Likewise, WT mice transplanted with SPARC null bone marrow developed very little fibrosis despite SPARC expression by resident cardiac cells. Interestingly, SPARC-null mice with WT bone marrow showed an increase in the cardiac macrophage population as well as increased levels of VCAM-1 expression at two weeks post TAC versus WT mice with SPARC-null bone marrow. In conclusion, SPARC-dependent macrophage recruitment to the myocardium is a significant factor to the development of fibrosis after TAC and may offer a novel target for future strategies in the treatment of HFpEF.

Rights

All rights reserved. Copyright is held by the author.

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