Cardiac fibroblasts (CF) and cardiac myocytes (CM) play central roles in the cardiac remodeling response that occurs in many cardiovascular diseases. It entails CM hypertrophy, CF activation and increased extracellular matrix deposition, and often leads to heart failure and arrhythmias. CF increasingly attract attention as therapeutic targets but they have received much less attention than CM so far. The Gq signaling pathway is well known to play a central role in cardiac remodeling and to lead to pro-fibrotic effects in CF. However, there is a fundamental gap in understanding of the mechanisms that regulate Gq signaling in CF and how Gq signaling in CF crossregulates CM and affects the cardiac remodeling response to hemodynamic stress. We recently showed that the negative Gq regulator RGS2 (Regulator of G protein Signaling 2) is expressed in CF and uniquely susceptible to regulation compared to other RGS isoforms. We also show that RGS2 is up- regulated by cAMP, which is at the center of the Gs signaling pathway with well known anti-fibrotic effects. In addition, cGMP is known to phosphorylate RGS2 and also exert anti-fibrotic effects. However, the underlying mechanisms of action and potential crosstalk with the Gq signaling pathway in CF are not yet well understood. The long-term goal of this research program is to advance understanding of the regulation of Gq signaling in CF and its role in determining the cardiac remodeling response to stress. Using multi-scale experimental approaches will test our central hypothesis that Gq-mediated signaling in CF and its regulation by cyclic nucleotides not only determines CF responses but crossregulates CM function and thereby influences cardiac remodeling.
The Specific Aims are: (1) To determine the role of RGS2 as a mediator of anti-fibrotic cAMP effects in adult rat ventricular CF and the mechanisms of this novel crosstalk between the Gs and Gq signaling pathways; (2) To determine the effect of altered Gq signaling in CF on CM and the integrated functional response of cardiac microtissues; and (3) To determine the effect of fibroblast-restricted RGS2 deletion on Gq- mediated cardiac remodeling in vivo. We will use cardiac microtissues and intact mice, in which Gq signaling can be selectively altered in CF, as novel experimental models. Using multidisciplinary approaches, we will characterize structural (fibrosis and hypertrophy) and electrical remodeling responses, assess functional consequences on contractile function and heart rate regulation, and determine underlying mechanisms. Further innovation lies in addressing the role of CF-to-CM cross-regulation on the integrated remodeling response. The proposed study is significant, because the new insights we will gain about Gq-mediated signaling in CF, its regulation and the resulting consequences for CF, CM and their integrated remodeling response are expected to aid in the development of new strategies targeting cardiac remodeling for heart failure treatment/prevention.
Cardiac remodeling is defined as alterations in the size, shape and function of the myocardium in response to changes in mechanical, chemical and/or electrical signals under pathological conditions. It often leads to heart failure, the leading caus of death in the industrialized world. In addition to diminished pump function, the remodeled heart is associated with lethal arrhythmias and sudden cardiac death. Activation of cardiac myocytes (CM) and fibroblasts (CF) via the Gq signaling pathway is well known to play an important role during structural and electrical remodeling. While CM have garnered most of the attention in the past few decades, CF are important therapeutic targets as well, because - like CM - they are key determinants of structural, mechanical and electrical characteristics in the myocardium. However, there is a fundamental gap in the understanding of the mechanisms that regulate Gq signaling in CF, and little is known about the cross- regulation between the two major cell types in the heart. The proposed study will advance understanding of how Gq-mediated signaling and function in CF are regulated, affect CM function via cross-regulation, and determine the remodeling response in vivo. The insights that will be gained with the proposed study are expected to aid in the design of enhanced strategies to delay or prevent Gq-mediated structural and electrical remodeling in response to hemodynamic stress.
