Research Interests

The cardiac extracellular matrix or “matrix”, provides structural support for contractile muscle cells (cardiac myocytes), and allows the heart to effectively contract and thereby function as an engine to pressurize the pulmonary and systemic circulations. Recent work indicates that this basic description is expanded.
Matrix and cardiac function Historically, cardiac matrix proteins (including fibrillar and non-fibrillar collagen species, fibronectins, laminin, integrins, various proteoglycans such as hyaluronate as well as chondroitin and heparan sulphate) have been confined to the role of cellular scaffolding with the sole function of physical connection of cardiac myocyte-myocyte and myocyte-capillary surfaces and for the transmission of contractile force. The development of our understanding of these proteins in recent years has yielded new concepts pertaining to the function of the cardiac matrix including its role in the relaxation phase of the cardiac muscle contraction cycle (lusitropic function), in which they may contribute to active expansion of contracted muscle cells. The matrix thereby confers functional suction to the relaxing right (pulmonary) and left (systemic) ventricular chambers. Perhaps just as important in its “macro” role within the context of cardiac function, the matrix participates in regulation gene expression and behavior via interaction with specific transmembrane cellular receptors. For example, major matrix components interact closely with parenchymal cells via specific connecting proteins on the cell surface, which impact on the phenotype of the cell (i.e., differentiation - itself a function of subsets of activated gene expression), as well as in adhesion and migration among other cellular functions. The members of our lab and I have studied matrix deposition in heart failure since the lab’s inception within the Department of Physiology in 1992.
Ongoing work: myofibroblasts and heart failure Our research (Ian M.C. Dixon and staff, Laboratory of Molecular Cardiology) addresses matrix remodeling of heart tissue concomitant to the development of cardiovascular disease. Roughly half of our projects address the fate of the matrix in healthy and diseased hearts, and together with serial (2D echocardiography) data on cardiac function, serve as end-points in manipulation of key signaling molecules that impact on matrix distribution. As cardiac fibroblasts and myofibroblasts are the sole source for fibrillar collagens and other matrix components, we have dedicated a large effort to primary culture of these cells. Essentially, we and others have discovered that normally quiescent fibroblasts “fall” into the phenotype of the muscular, contractile and hypersecretory variant (myofibroblast) when plated at low density at P0 in the presence of serum. As it is myofibroblasts that are the physiologically relevant cell type in cardiac repair associated with so-called infarct scar thinning after myocardial infarction (MI), our efforts during the past 6 years have focused on these primary cardiac cells as an experimental model. Thus we are able to routinely combine classic physiology with methods in cell biology and molecular biology to address issues relevant to matrix remodeling in post-MI heart.

Congestive heart failure subsequent to myocardial infarction (heart attack) remains the primary cause for the development of chronic congestive heart failure in North. America, at tremendous cost to society. The importance of congestive heart failure needs no emphasis as the prognosis for heart failure patients is grave, despite recent advances in pharmaceutical therapies. Heart failure is usually accompanied by inappropriate cardiac growth (cardiac hypertrophy) which involves multiple changes to the fine structure of the heart including the cardiac matrix. Although rough descriptions of generalized cardiac fibrosis (high levels of matrix) in clinical heart failure and experimental models of failure exist, the precise nature of transcriptional and translational control of key matrix proteins is unclear.
Final word on specific ongoing projects and peculiarities associated with cardiac repair The heart is an endocrine organ, and our lab has spent some time describing particularly germane signaling cascades in myofibroblast stimulation. Cardiac wound healing post-MI is unlike that of the healing of a skin abrasion, as the myofibroblasts appear early on but do not go through a round of mass apoptosis or necrosis after classical wound healing is complete. That is, myofibroblasts persist for many years thereafter in the healed infarct scar, well beyond the acute healing phase, via an unknown mechanism. This fact may be at the basis for difficulties associated with reintroducing myocytes to the site of infarction as an alternative mode of cardiac repair in post-MI heart. As heart failure is associated with alterations in circulating and local cardiac hormone metabolism, we are investigating hormonal i.e., angiotensin II, as well as cardiotrophin-1 (CT-1, a cytokine), TGF-?1 (another cytokine) and TNF-? involvement in the regulation of cardiac fibrosis. We have published a number of papers that deal with “stand-alone” or shared signaling among these systems in cardiac myofibroblasts, and the putative impact of these signals in the development of cardiac fibrosis and heart failure. We are particularly interested in 1. myofibroblast matrix synthesis; 2. myofibroblast migration to sites of wound healing; 3. the balance of signaling that effectively allows myofibroblasts to “repopulate” the healing infarct zone, and 4. the signals that essentially allow the maintenance of myofibroblasts in the healed infarct scar for months and years (and likely decades) after classical wound healing is complete. Finally, we are 5. pursuing the utility of naturally occurring anti-fibrotic peptides such as Ski (a Smad corepressor), C184M and I-Smad 7 in manipulation of myofibroblast activation in the heart.

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