Both G-protein coupled receptor signaling and calcium signaling play critical roles in the development of cardiac hypertrophy and progression to heart failure. In non-contractile cell-types increased intracellular calcium concentration directly regulates proliferation, differentiation, metabolism, motility, and cell death through the action of unique calcium-dependent signaling proteins. Many of these calcium-dependent regulatory processes are conserved in cardiac myocytes, although the physiologic relevance of """"""""reactive"""""""" calcium signaling remains a nebulous concept in the heart given the highly specialized manner in which calcium cycling is regulated for excitation contraction (EC)-coupling. While it is theoretically possible that total contractile calcium associated with EC-coupling regulates calcium sensitive signaling proteins such as calcineurin, calmodulin dependent kinases (CaMK) and PKC, it seems unlikely since such a mechanism would not discriminate between inotropy and signaling. Thus, specialized pools of calcium need to be evoked to account for the regulation of calcium-sensitive signaling proteins. One potential source of calcium for specialized signaling in ventricular myocytes is through the inositol 1,4,5 trisphosphate (IP3) receptor calcium channel. While the biologic importance of these channels is well established in non-contractile cells as the source of calcium for most signaling events, its functional role in cardiac myocytes remains more elusive. However, cardiac hypertrophy and heart failure are characterized by an increase in IP3R expression and activity, suggesting it might play an important disease-signaling role. Our preliminary data suggests that increased IP3 receptor activity in transgenic mice induces cardiac hypertrophy and enhances hypertrophy after stimulation. Thus, we hypothesize that enhanced IP3 mediated calcium release in disease regulates unique calcium sensitive signaling pathways and plays a crucial role in development of cardiac hypertrophy and progression to heart failure. To investigate this hypothesis, we will examine the phenotype of type2 IP3 receptor inducible transgenic mice with enhanced IP3 mediated calcium release as well as IP3 sponge transgenic mice in which IP3 signaling will be eliminated in myocytes by trapping IP3.
Cardiovascular disease remains the number one cause of mortality in the Western world, with heart failure representing the fastest growing subclass over the past decade. Whereas antagonists for G-protein coupled receptors (GPCR) are beneficial treatments for chronic heart failure, the five year survival of patients on such medication remains dismal and suggests that new drugs are needed that target other disease pathways in the heart. Calcium plays an extremely important role in heart failure in terms of contraction, hypertrophy and cell death, yet correlation between calcium and GPCR signaling remains nebulous. In this proposal, we will focus on the inositol 1,4,5 trisphosphate (IP3) receptor as the key linkage between GPCR signaling and alterations in calcium in the myocyte that can induce disease. We will utilize genetically engineered gain- and loss- of function mice for IP3 receptor signaling in the heart and attempt to decipher its role in cardiac hypertrophy and progression of heart failure.
