STAT3 and Endothelial Cell—Cardiomyocyte Dialog in Cardiac Remodeling

Figure 1. STAT3 as a sentinel of stress. Accumulating evidence reveals that STAT3 is located within various cellular compartments, or relocates there with stress stimuli. In this capacity, STAT3 serves to maximize efficient respiration, limit ROS generation, and prevent apoptosis with ischemia-reperfusion (mitochondria and endoplasmic reticulum). In the nucleus, constitutive, and enhanced STAT3 modulates cytokine and inflammatory signaling. A pool of STAT3 constitutively associated with βIV-spectrin at intercalated discs responds to increased wall stress on the heart by remodeling of the extracellular matrix through gene induction. See text and previous reviews (1, 3) for additional details. Images are from Servier Medical Art (https://smart.servier.com/).

Figure 2. STAT3 and crosstalk between endothelial cells and cardiomyocytes of the heart. Loss of STAT3 in cardiomyocytes leads to a decrease in SOD2 and Bcl-xL expression, resulting in increased reactive oxygen species (ROS) formation and apoptosis, respectively. Increased ROS is implicated in the upregulation of cathepsin D and formation of a shortened version of prolactin in peripartum cardiomyopathy, which induces miR-146a in endothelial cells. miR-146a has angiotoxic actions by targeting NRAS, which encodes for N-Ras that may act downstream of the VEGF or EGF receptors. Released in endosomes, endothelial miR-146a is taken up by cardiomyocytes and downregulates Notch1 (with beneficial or harmful effects that are context dependent), inflammatory Irak1, and the cytoprotective neuregulin receptor ErbB. Loss of cardiomyocyte STAT3 also upregulates miR-7a-5p that targets ErbB, as well as miR-199a-5p. Upregulation of miR-199a-5p decreases expression of the glucose transporter GLUT4 and leads to an increase in the endogenous inhibitor of eNOS and endothelial function, asymmetric dimethylarginine (ADMA), by impeding the ubiquitin-proteasome system (UPS). Impairment of UPS is associated with…