Role of caveolin-1 in heart extracellular matrix deposition and remodelling upon myocardial infarction
Authors:   Mechanoadaptation and caveolae biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain 2Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, Pulgarín-Alfaro Marta , Catalá Mauro ,   Mechanoadaptation and caveolae biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain 2Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, Navarro-Lérida Inmaculada ,   Mechanoadaptation and caveolae biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain 2Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, Mercader Nadia ,   Development of the epicardium and its role during regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, Flores Ignacio ,   Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, Garrido Carlos ,   Mechanoadaptation and caveolae biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain 2Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain,   Genetic control of organ development and regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
Published: June 2022

Introdution: Changes in tissue stiffness or forces transmitted across tissues drive cell functions and behaviour. Cardiovascular system is inherently mechanical, and how its cells and tissues interplay with mechanical forces are an important aspect of its physiology. For example, upon heart damage, the non-injured myocardium is subjected to mechanical overload to preserve heart functionality. Caveolin-1 (Cav1) is an essential constituent of caveolae, flask- shaped invaginated nanodomains of the plasma membrane that act as mechanosensing and mechanoadapting structures through tension-driven flattening and disassembly and membrane trafficking. Cav1 phospho-Tyr14 is an important regulatory node that regulates caveolae internalization and specific downstream functions, but its relevance to cardiac remodelling and function has not been explored. In this study, we have assessed the role of Cav1 on mechanical adaptation to myocardial infarction, specifically on scar establishment and remodelling. Matherial and methods: To study the role of Cav1 on cardiac regeneration potential and extracellular matrix (ECM) remodelling ability upon myocardial infarction (MI), mice that express a non-phosphorylatable form of Cav1 on Tyr14 (Cav1Y14F/Y14F) were used. As a model of MI, postnatal day 1 mice were subjected to heart cryoinjury. Mice were anesthetized by hypothermia, lateral thoracotomy was performed to expose the heart and a metal probe cooled in liquid nitrogen was applied to the left ventricle. The deposition of fibrotic tissue at 7 days postinjury was assessed by H&E and Picrosirius Red histological stainings. Proteomics analysis of cryoinjured hearts was performed. Cardiac lesions were further characterized by immunofluorescence for several markers (CD68, αSMA, Cav1, pHis3, etc.). Results: We previously found that Cav1 is a pivotal regulator of physical ECM remodelling, determining cell migration and tissue fibrosis, and also that specific non-collagen ECM components, are sorted into exosomes through a Cav1- dependent mechanisms. Proteomics analysis of infarcted hearts suggest that Cav1 mutant mice present an altered deposition of ECM proteins, which might impair the recovery of cardiac function. In agreement with this, aberrant histopathological features were observed in scars formed in mutant hearts. Increased macrophage density was observed in Cav1Y14F/Y14F mice, but no significant differences on cell proliferation were found. Conclusions: Here, we provide several evidences suggesting that Cav1 is a key player on mechanoadaptation and machanoresponse in challenged hearts and that Cav1 phospho-Tyr14 is involved in ECM deposition and remodelling and immune infiltration in cryoinjured hearts.