Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis.

Aberrant activation of cardiac fibroblasts is the main cause and character of cardiac fibrosis, and inhibition of cardiac fibrosis becomes a promising treatment for cardiac diseases. Platelet-activating factor (PAF) and Hippo pathway is recently recognized as key signaling mechanisms in cardiovascular diseases. In this study we explored the potential roles of PAF and Hippo signaling pathway in cardiac fibrosis. Myocardial infarction (MI) was induced in mice by left anterior descending artery ligation. After 28 days, the mice were sacrificed, and the hearts were collected for analyses. We showed that PAF receptor (PAFR) and yes-associated protein 1 (YAP1, a key effector in the Hippo pathway) were significantly increased in the heart of MI mice. Increased expression of PAFR and YAP1 was also observed in angiotensin II (Ang II)-treated mouse cardiac fibroblasts. In mouse cardiac fibroblasts, forced expression of YAP1 increased cell viability, resulted in collagen deposition and promoted fibroblast-myofibroblast transition. We showed that PAF induced fibrogenesis through activation of YAP1 and promoted its nuclear translocation via interacting with PAFR, while YAP1 promoted the expression of PAFR by binding to and activating transcription factor TEAD1. More importantly, silencing PAFR or YAP1 by shRNA, or using transgenic mice to induce the conditional deletion of YAP1 in cardiac fibroblasts, impeded cardiac fibrosis and improved cardiac function in MI mice. Taken together, this study elucidates the role and mechanisms of PAFR/YAP1 positive feedback loop in cardiac fibrosis, suggesting a potential role of this pathway as novel therapeutic targets in cardiac fibrosis.

Biocompatible Fe-Si Nanoparticles with Adjustable Self-Regulation of Temperature for Medical Applications.

Because of the noninvasive, locally selective potential of thermal energy, considerable effort has been focused on the use of an external, alternating magnetic field for conversion of magnetic work to heat with iron oxide nanoparticles. However, proper regulation of thermal energy remains a challenge because of the lack of feedback from the local temperature change to the external power supply. Here, we show development of smart magnetic nanoparticles composed of Fe and Si with intrinsically tunable heat generation capability. They were engineered to possess an adjustable magnetic transition temperature through tuning the exchange between Fe atoms by incorporation of silicon atoms. They show relatively high magnetic moment. Moreover, their biocompatibility was established in several cell lines. The nanoparticles were also combined with a thermosensitive polymer, which had the capability to release of molecules with a magnetic stimulus, thereby providing a platform for locally controlled, drug release.