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Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusion We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFβ signaling involves its binding to TGFβ receptor type II (TGFβRII), which recruits TGFβ receptor type I (TGFβRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFβ levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFβ signaling at different steps, affecting different components. Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFβ signaling pathway, for instance cardiac dysfunction and heart failure. [ABSTRACT FROM AUTHOR]