Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research.

The extracellular matrix (ECM) is a complex and dynamic entity that drives the formation and development of the cardiovascular system, determines critical aspects of cardiovascular performance, and plays key roles in the initiation and progression of abnormal cardiovascular function with aging and disease. Microscopic studies in the late 1700s identified fibrous structures surrounding cells, which led scientists to conclude that the ECM was primarily a foundational unit to provide support.1 Unfortunately, this historic view that the ECM is a static scaffold is still to this day held by many who are not in the field. Using molecular, cell based, and dynamic imaging systems, however, experts now recognize that the ECM is an ever-changing component that responds to normal and abnormal molecular and biophysical cues and, in turn, drives changes in overall cardiovascular structure and function. The ECM contains structural and nonstructural proteins, interacts dynamically with unique and differentiating cell types, serves as a reservoir and processing site for signaling molecules, and forms communication corridors for both protein and genetic information. Thus, the ECM is a diverse entity that presents a novel and exciting research frontier that could yield improvements in diagnostics, prognostics, therapeutics, and prevention of cardiovascular disease. A recent Pubmed search (accessed August 23, 2016) using the terms ECM and cardiovascular, cardiac, or vascular revealed that this field has been growing annually since the 1990s (Figure). Driving forces for the increased interest in ECM research include the recognition of biological and pathophysiological importance, improvements in biochemical, cellular, and molecular techniques by which to study this complex unit, and advances in the capacity at microscopic and macroscopic levels to provide greater insight into the dynamically changing ECM. Using combinatorial approaches, ECM research can be explored at greater depths than previously possible. This editorial forms a coalescence of discussions by …

[1]  Viola Vogel,et al.  Cell fate regulation by coupling mechanical cycles to biochemical signaling pathways. , 2009, Current opinion in cell biology.

[2]  D. Sheppard,et al.  Integrin-mediated regulation of TGFβ in fibrosis. , 2013, Biochimica et biophysica acta.

[3]  M. Zile,et al.  Integrating the myocardial matrix into heart failure recognition and management. , 2013, Circulation research.

[4]  N. Frangogiannis,et al.  Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. , 2016, Journal of molecular and cellular cardiology.

[5]  Yonggang Ma,et al.  Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling. , 2016, Journal of molecular and cellular cardiology.

[6]  A. Su,et al.  Harnessing the heart of big data. , 2015, Circulation research.

[7]  Mikaël M. Martino,et al.  Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing , 2014, Science.

[8]  M. Czubryt,et al.  Gaining myocytes or losing fibroblasts: Challenges in cardiac fibroblast reprogramming for infarct repair. , 2016, Journal of molecular and cellular cardiology.

[9]  I. Dixon,et al.  Cardiac Fibrosis and Heart Failure—Cause or Effect? , 2015 .

[10]  B. Aronow,et al.  Genetic lineage tracing defines myofibroblast origin and function in the injured heart , 2016, Nature Communications.

[11]  Z. Kassiri,et al.  Extracellular matrix communication and turnover in cardiac physiology and pathology. , 2015, Comprehensive Physiology.

[12]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[13]  J. Holmes,et al.  Computational modeling of cardiac fibroblasts and fibrosis. , 2016, Journal of molecular and cellular cardiology.

[14]  F. Spinale,et al.  Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. , 2014, Biochemical pharmacology.

[15]  J. Holmes,et al.  Physiological Implications of Myocardial Scar Structure. , 2015, Comprehensive Physiology.

[16]  B. Hinz The extracellular matrix and transforming growth factor-β1: Tale of a strained relationship. , 2015, Matrix biology : journal of the International Society for Matrix Biology.

[17]  N. Frangogiannis,et al.  The Extracellular Matrix Modulates Fibroblast Phenotype and Function in the Infarcted Myocardium , 2012, Journal of Cardiovascular Translational Research.

[18]  Yu-Fang Jin,et al.  Transformative Impact of Proteomics on Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association , 2015, Circulation.

[19]  Z. Kassiri,et al.  ADAMs family and relatives in cardiovascular physiology and pathology. , 2016, Journal of molecular and cellular cardiology.

[20]  B. Hinz,et al.  The myofibroblast matrix: implications for tissue repair and fibrosis , 2013, The Journal of pathology.

[21]  J. Holmes,et al.  Emergence of Collagen Orientation Heterogeneity in Healing Infarcts and an Agent-Based Model. , 2016, Biophysical journal.

[22]  R. Visse,et al.  Matrix Metalloproteinases Regulation and Dysregulation in the Failing Heart , 2002 .

[23]  S. Prabhu,et al.  The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. , 2016, Circulation research.

[24]  N. Rosenthal,et al.  Revisiting Cardiac Cellular Composition. , 2016, Circulation research.

[25]  Francis G Spinale,et al.  Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. , 2007, Physiological reviews.

[26]  K. Yutzey,et al.  Cardiac Fibrosis: The Fibroblast Awakens. , 2016, Circulation research.

[27]  M. Lindsey,et al.  Translating Koch's postulates to identify matrix metalloproteinase roles in postmyocardial infarction remodeling: cardiac metalloproteinase actions (CarMA) postulates. , 2014, Circulation research.

[28]  Z. Werb,et al.  Extracellular matrix degradation and remodeling in development and disease. , 2011, Cold Spring Harbor perspectives in biology.

[29]  B. Hinz,et al.  Mechanical control of cardiac myofibroblasts. , 2016, Journal of molecular and cellular cardiology.

[30]  Stephane Heymans,et al.  Myocardial Extracellular Matrix: An Ever-Changing and Diverse Entity , 2014, Circulation research.

[31]  Xenophon Papademetris,et al.  Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in a Porcine Model of Postinfarct Remodeling: Relationship to Myocardial Dysfunction , 2011, Circulation. Cardiovascular imaging.

[32]  N. Frangogiannis,et al.  Fibroblasts in myocardial infarction: a role in inflammation and repair. , 2014, Journal of molecular and cellular cardiology.

[33]  Michael E. Hall,et al.  Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. , 2014, American journal of physiology. Heart and circulatory physiology.

[34]  M. Lindsey,et al.  Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence. , 2015, Cardiovascular research.

[35]  Z. Kassiri,et al.  Tissue inhibitor of metalloproteinases (TIMPs) in heart failure , 2012, Heart Failure Reviews.

[36]  Andrew W. Trafford,et al.  Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling , 2016, Journal of molecular and cellular cardiology.

[37]  N. Frangogiannis Matricellular proteins in cardiac adaptation and disease. , 2012, Physiological reviews.