Ca2+ plays a pivotal role in both excitation contraction-coupling (ECC) and activation of signaling pathways in the myocardium. However, it remains a mystery how Ca2+-dependent signaling pathways are activated in myocytes given the overwhelming cytosolic Ca2+ concentrations that are achieved to mediate contraction. One possibility is that specialized pools of Ca2+ have evolved that are spatially distinct from the cytoplasmic Ca2+ transient thereby generating a restricted signaling microdomain. Another possibility that will explored here is that global changes in diastolic Ca2+ Is a primary means of driving the cardiac hypertrophic response and ensuing heart failure, such as through calcineurin-NFAT signaling. Moreover, heart failure is often associated with elevations in total intracellular Na+ levels in adult myocytes. This elevation in Na* can secondarily drive Ca2+ elevations through effects on NCX1. Here we will examine the hypothesis that elevations in Na+ can enhance the cardiac hypertrophic response and disease by secondarily enhancing diastolic Ca2+ levels. To examine this hypothesis in Specific Aim#1 we will generate transgenic mice with enhanced Na* influx, while in Specific Aim #2 we will generate and analyze transgenic and gene-targeted that are manipulated for NCX1 and NKA (Na+ /K+ ATPase). When coupled with careful measurements of intracellular Na and Ca2+ , these first 2 aims will determine if and how diastolic Ca2+ programs hypertrophy through calcineurin-NFAT signaling in the heart. Finally, Specific Aim #3 will investigate the role that the mitochondrial permeability transition pore (MPTP) plays in regulating mitochondrial Ca2+ and propensity toward cardiomyopathy.

Public Health Relevance

of this application is rooted in the fundamental issue of how Ca2+ signaling pathways are controlled in the heart, which is of major medical importance considering the centrality that PKCs, CaMKll, and calcineurin play in controlling pathologic remodeling and heart failure. A better understanding of how Ca2+ regulates both contraction and signaling in a contractile cell, such as a cardiac myocyte, could reveal microdomain regulatory mechanisms that control hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL080101-08
Application #
8496855
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$386,834
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Ljubojevic, Senka; Bers, Donald M (2015) Nuclear calcium in cardiac myocytes. J Cardiovasc Pharmacol 65:211-7
Bers, Donald M (2014) Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction. Annu Rev Physiol 76:107-27
Xie, Yuanfang; Grandi, Eleonora; Bers, Donald M et al. (2014) How does ?-adrenergic signalling affect the transitions from ventricular tachycardia to ventricular fibrillation? Europace 16:452-7
Correll, Robert N; Eder, Petra; Burr, Adam R et al. (2014) Overexpression of the Na+/K+ ATPase ?2 but not ?1 isoform attenuates pathological cardiac hypertrophy and remodeling. Circ Res 114:249-56
Myles, Rachel C; Wang, Lianguo; Bers, Donald M et al. (2014) Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart. J Physiol :
Sankar, Natesan; deTombe, Pieter P; Mignery, Gregory A (2014) Calcineurin-NFATc regulates type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) expression during cardiac remodeling. J Biol Chem 289:6188-98
Walther, Stefanie; Pluteanu, Florentina; Renz, Susanne et al. (2014) Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177. Am J Physiol Heart Circ Physiol 307:H689-700
Zhang, Dai-Min; Chai, Yongping; Erickson, Jeffrey R et al. (2014) Intracellular signalling mechanism responsible for modulation of sarcolemmal ATP-sensitive potassium channels by nitric oxide in ventricular cardiomyocytes. J Physiol 592:971-90
Kapoor, Nidhi; Maxwell, Joshua T; Mignery, Gregory A et al. (2014) Spatially defined InsP3-mediated signaling in embryonic stem cell-derived cardiomyocytes. PLoS One 9:e83715
Morotti, S; Edwards, A G; McCulloch, A D et al. (2014) A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII. J Physiol 592:1181-97

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