Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology

Abstract

Despite significant advances in treating heart disease, heart failure remains a major cause of morbidity and mortality. Regardless of the initiating cause(s), heart failure is associated with disruptions in the myocardial extracellular matrix (ECM). ECM is a dynamic structure and its physiological turnover is mediated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Research in the past two decades has revealed that the function of ECM extends beyond its role in providing structural support. Similarly, ECM regulatory proteins, MMPs and TIMPs, have been demonstrated to play diverse and ECM-independent roles in tissue remodeling and homeostasis. ECM is a network structure that in addition to providing structural support, serves as an extracellular reservoir for a number of growth factors and cytokines, and plays a central role in interstitial transport of different molecules (hormones, growth factors, drugs, etc.). This is mainly through the action of nonstructural ECM components, proteoglycans and matricellular proteins, which are also critical in cell-ECM interactions and overall ECM remodeling. As such, sustaining the ECM integrity is not only critical in preserving cardiac geometry and function, it is essential in ensuring optimal delivery of different molecules to their site of action. Further, ECM composition and integrity in disease should be considered in designing drugs with a specific site of action. In this review article, we provide an overview of the ECM structure, components, its function in interstitial transport, heart disease-dependent ECM remodeling, and the potential therapeutic approaches in preserving the diseased myocardial ECM and cardiac function.

Atrial structure, function and arrhythmogenesis in aged and frail mice

“…MMPs are involved in the processing and degradation of collagen (and other extracellular matrix proteins) while TIMPs function to inhibit the activity of MMPs3336373839.…”

“…We initially focused on MMP2 and MMP9 as these are key gelatinases in the heart that play an important role in the degradation of collagens38. When measured as a function of age, MMP2 expression was not changed in the right atrium ( P  = 0.38), but was reduced ( P  < 0.001) in the left atrium of aged mice (Supplemental Fig.…”

Lamellipodia are critical for haptotactic sensing and response

“…It has long been known that cells can migrate up a gradient of adhered substrate (haptotaxis) in vitro (Carter, 1965), but the cellular and molecular mechanisms of this process are poorly understood. Haptotaxis is likely to contribute to many physiological and pathophysiological events, such as cutaneous wound healing (Sawicka et al, 2015;Clark, 1990), response to cardiovascular disease (Takawale et al, 2015), atherosclerosis and cancer progression (Kostourou and Papalazarou, 2014;Aznavoorian et al, 1990;Wolf and Friedl, 2011). Understanding the mechanism of haptotaxis will be crucial for dissecting the relative contributions of various directional migration cues during these events.…”

Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research

“…3 Fibrosis in response to MI is scar ECM that replaces dead myocytes (reparative fibrosis), and this post-infarction scar displays notable variability in collagen content and arrangement. 4 …”