Biomedical Summer Undergraduate Research Experience Program (B-SURE)
The University of Texas Health Science Center at San Antonio (UTHSCSA)

My laboratory is dedicated to performing cardiovascular-oriented research that involves:

1. developing multidimensional approaches to examine the mechanisms whereby the left ventricle responds to injury;
2. applying the knowledge gained to develop therapeutic strategies to prevent, slow, or reverse the progression to heart failure; and
3. disseminating our results to scientific and medical communities.

General Aims. The focus of my laboratory is cardiac extracellular matrix biology, particularly changes to the matrix that are the cause or effect of pathophysiological processes. These changes include cell-matrix interactions, which both affect and react to processes involved in tissue repair. My laboratory primarily uses the murine model of myocardial infarction (MI). In addition to physiological parameters, we also measure biochemical, cell biological, and proteomic outputs. The main focuses of my laboratory are:

1. the role of macrophage-derived MMPs in LV remodeling post-MI
2. the role of the cardiac fibroblast in the remodeling process
3. the influence of aging on LV remodeling

1. The role of macrophage-derived MMPs in LV remodeling post-MI
 

This is a currently funded R01 (NIH/ NHLBI HL075360) with total direct costs of $1,250,000.
 

Adverse remodeling of the left ventricle (LV) occurs following a myocardial infarction (MI) and serves to decrease LV function, ultimately progressing to congestive heart failure (CHF). CHF is a primary complication and cause of death post-MI. Changes to the extracellular matrix (ECM) serve as principle regulators in the remodeling process through both direct and indirect mechanisms. One mechanism involves the upregulation of matrix metalloproteinases (MMPs), a family of enzymes that degrade components of the ECM to regulate remodeling events. In response to an ischemic challenge, the LV undergoes an initial inflammatory phase that precipitates the influx of macrophages into the necrotic zone to release cytokines and perform phagocytic functions. While these events are well understood, additional roles for the macrophage and macrophage-specific MMP expression in the LV remodeling process have not been explored. Although both cardiac resident and non-resident (inflammatory cells) produce MMPs, the macrophage is a predominant source of MMP-7 and MMP-9, likely candidates for participation in remodeling events. In addition, the 3 to 7 day post-MI time point, when macrophage infiltration peaks, is concomitant with a high rate of mortality.

Direct MMP-7 and MMP-9 effects on LV remodeling occur through proteolysis of matrix substrates such as collagen and fibronectin, which herald signaling cascades to amplify the inflammatory response and induce LV dilation (Figure, phase I). In addition to a direct matrix effect, macrophage-derived MMPs -7 and -9 potentially proteolyze additional substrates and serve dual roles in remodeling through processing of bioactive molecules (Figure, phase II). This indirect effect would serve as an additional level of regulation to amplify the response to MI. Accordingly, the long-term goal of this project is to define upstream mechanisms to fine-tune the remodeling process through manipulation of the macrophage and macrophage-derived MMPs. The central hypothesis is that macrophage-derived MMP-7 and MMP-9 coordinate the macrophage response during LV remodeling through proteolytic cleavage of matrix and non-matrix substrates.

2. The role of the cardiac fibroblast in the remodeling process

Adverse remodeling of the left ventricle (LV) is a common structural event following myocardial infarction (MI). LV remodeling contributes to the development of congestive heart failure (CHF) through changes in wall structure and chamber geometry, which ultimately can give rise to pump failure. An important consequence of MI is a specific set of changes to extracellular matrix (ECM) composition and organization. The LV myocardial fibroblast is a principal cell type regulating changes within the ECM. Under normal conditions, the fibroblast maintains ECM integrity and myocardial architecture by communicating via integrin receptors. Integrins are cell-surface heterodimer receptors composed of an a and b subunit that together mediate direct interactions between the cytoskeleton and the matrix. Past studies provide evidence that a sequential series of signaling events (both biological and mechanical) give rise to fibroblast activation post-MI. While the sequence of activation is incompletely understood, one likely cascade of events is a coordination of early (TNFa), intermediate (endothelin-1), and late components (TGFb) that stimulate particular steps in the activation cascade and involve specific changes in protein expression and functions (Figure). Using functional assays coupled with proteomic technology, we will test the hypothesis that a specific regional and temporal set of biological and mechanical events locally activate fibroblasts post-MI.

Legend. Fibroblast activation occurs in a sequential progression to regulate ECM turnover following myocardial infarction. Examples of input factors are illustrated on the left and output factors on the right. Changes in fibroblast phenotype provide a mechanism for altered ECM structure and function.

3. The influence of aging on LV remodeling

In the elderly, myocardial infarction (MI) is associated with increased infarct expansion and increased morbidity and mortality compared with younger patients. Following MI, the left ventricle (LV) undergoes robust and adverse remodeling to remove necrotic myocytes and generate a scar. The remodeling response involves the degradation of extracellular matrix (ECM) through increased activity of matrix metalloproteinases (MMPs). MMP-mediated ECM degradation liberates matricryptins, biologically active peptide cleavage products of ECM proteins. Matricryptins signal changes in cell proliferation, migration, and ECM protein expression. A principal myocardial cell type and a principal inflammatory cell type that respond to matricryptin stimulation and are crucial for remodeling are the fibroblast and macrophage, respectively. Therefore, altered ECM turnover resulting from differential matricryptin production and cell function may explain the infarct expansion differences in the elderly.

In the LV of old mice, MMPs –3, -8, -9, -12, and –14 levels increase, collagen levels are altered, and myocardial fibroblast proliferation decreases. ECM substrates in common to these MMPs are collagen I (a fibrillar collagen), fibronectin (a non-collagen ECM component), and laminin (a basement membrane ECM component). Furthermore, specific matricryptins generated from these ECM proteins have demonstrated roles in ECM and MMP synthesis and cell function. The overall goal of this proposal, accordingly, is to dissect out the age-related differences in matricryptin production that yield differences in LV structure and function post-MI (Figure).

Legend. Age-related differences in MMPs generate a differential matricryptin profile, which provide a mechanism for altered ECM structure and LV function post-MI.

Our central hypothesis is that aging induces an altered MMP portfolio that yields a differential matricryptin profile, which in turn alters ECM structural and LV functional responses to MI.

Merry Lindsey's Web Page.