Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function

Abstract

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodeling 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 signaling 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 remodeling. 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 program 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 signaling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusions We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program. Translational perspective Cardiac fibroblasts are the most prevalent cell type in the heart and play an important role in regulating post-myocardial infarction (MI) cardiac fibrosis. Excessive cardiac fibrosis causes ventricular stiffness leading to systolic/diastolic cardiac dysfunction and heart failure. Therefore, understanding the molecular mechanism of cardiac fibroblasts activation will help to modulate the post-MI fibrotic response and improve cardiac function. In our study, we show that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program.

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

“…Elevated YAP and downregulated upstream Hippo kinase LATS1 were determined in the left ventricular tissue of HF patients, which was associated with cardiac fibroblast proliferation [42]. Recent studies also identified the activation of YAP and TAZ in resident cardiac fibroblasts from preclinical MI models (Figure 2) [18,19,27]. YAP and TAZ can directly induce the differentiation of fibroblasts into pathologic myofibroblasts [27,28].…”

“…Understanding the mechanisms underlying fibrotic cardiac remodeling after injury remains a critical barrier to developing effective treatments for HF patients. An increasing number of studies have revealed important roles for Hippo signaling components in the development and progression of cardiac fibrosis [18][19][20]23,[27][28][29]35,37,39,[42][43][44][45][46][47][48]. While YAP/TAZ activation is crucial for driving cardiac fibrosis, their suppression was beneficial for preventing angiotensin II (AngII) or MI-induced fibrosis [18,19,29,44].…”

“…YAP and TAZ can directly induce the differentiation of fibroblasts into pathologic myofibroblasts [27,28]. Fibroblast-specific deletion of Yap/Taz using Col1a2 Cre(ER)T mice [18] or deletion of only Yap using Tcf21 MCM ;Yap F/F mice [19] showed reduced fibrotic and inflammatory responses in infarcted hearts. Similarly, Yap/Taz deletion resulted in an impaired profibrotic response in the fibroblasts from the infarcted heart.…”

“…Numerous cell types, including epithelial and endothelial cells are also able to transdifferentiate into myofibroblastic phenotype (such as epithelial-mesenchymal transition and endothelial-mesenchymal transition) during organ fibrogenesis [4]. Recent studies have implicated the contribution of Hippo signaling pathway components in the fibrosis of various tissues, including the lung [5][6][7], liver [8][9][10][11][12][13][14], kidney [15][16][17], and heart [18][19][20]. The Hippo signaling pathway was first identified and illustrated in Drosophila.…”

“…A growing number of studies have reported that the cascade components also play a critical role in fibrotic diseases. For example, the nuclear YAP/TAZ in resident cardiac fibroblasts obtained from preclinical myocardial infarction (MI) models [18,19,27], are sufficient to direct the transdifferentiation of cardiac fibroblasts into pathological myofibroblasts [27,28]. Similarly, YAP/TAZ are important regulators of pathological fibroblast activation in pulmonary fibrosis [5] and hepatic stellate cell activation in liver fibrosis [11][12][13][14].…”