In myocardial ischemia, pathologic release of norepinephrine (NE) from sympathetic nerves leads to arrhythmias and death. The mechanisms responsible remain obscure. The overall objective of this grant is to address the important biological issue of whether a local renin-angiotensin system (RAS) plays a significant role in exacerbating NE release in myocardial ischemia. Our preliminary results demonstrate that cardiac mast cells are a novel source of renin, the rate-limiting enzyme responsible for initiating ANG n formation. We hypothesize that degranulation of cardiac mast cells, as occurs in ischemia, is pivotal for activation of local RAS and ANG II formation in the proximity of neuronal ATi receptors (ATiR).
In Specific Aim I, we will characterize mast-cell renin from congenic controls (CC) of c-Kit knock out (KO) mice, and from cultured human mast cells (HMC-1). We will also investigate in normoxic and ischemic cardiac models from guinea-pigs, and CC and KO mice, whether locally synthesized ANG n from mast-cell-derived renin activates neuronal ATiR to elicit NE release and reperfusion arrhythmias. We have already ascertained in a cultured-cell model of ischemic sympathetic nerves, that exogenous ANG n stimulates neuronal Na+/H^ exchange (NHE) leading to excessive carrier-mediated NE release. Thus, in Specific Aim n we will study, in human neuroblastoma cells transfected with the cloned rat ATjA receptor (SH-SYSY-ATu), the signal transduction of this ANG H-mediated NHE stimulation. Experiments in SH-SYSY-ATiA cells demonstrate that stimulation of NHE and carrier-mediated NE release by AT)R activation occurs via a Ca +-dependent pathway. Accordingly, our investigation will focus on elucidating the role of PLC, Ca2+, PKC, and calmodulin in this Ca2+-dependent pathway. The overall premise of these experiments is that if we understand the patho-physiological basis for the formation of ANG n in the ischemic heart, and how ANG II exacerbates NE release, then we will also have identified potential therapeutic targets to alleviate ischemic arrhythmias and associated cardiac dysfunctions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073400-04
Application #
7383071
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$477,883
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
O'Connor, Nathan; Silver, Randi B (2013) Ratio imaging: practical considerations for measuring intracellular Ca2+ and pH in living cells. Methods Cell Biol 114:387-406
Veerappan, Arul; O'Connor, Nathan J; Brazin, Jacqueline et al. (2013) Mast cells: a pivotal role in pulmonary fibrosis. DNA Cell Biol 32:206-18
Morrey, Christopher; Brazin, Jacqueline; Seyedi, Nahid et al. (2010) Interaction between sensory C-fibers and cardiac mast cells in ischemia/reperfusion: activation of a local renin-angiotensin system culminating in severe arrhythmic dysfunction. J Pharmacol Exp Ther 335:76-84
Koda, Kenichiro; Salazar-Rodriguez, Mariselis; Corti, Federico et al. (2010) Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells. Circulation 122:771-81
Park-Min, Kyung-Hyun; Ji, Jong-Dae; Antoniv, Taras et al. (2009) IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol 183:2444-55
Morrey, Christopher; Estephan, Rima; Abbott, Geoffrey W et al. (2008) Cardioprotective effect of histamine H3-receptor activation: pivotal role of G beta gamma-dependent inhibition of voltage-operated Ca2+ channels. J Pharmacol Exp Ther 326:871-8
Machida, Takuji; Hamaya, Yukihiro; Izumi, Sachiko et al. (2008) Sphingosine 1-phosphate inhibits nitric oxide production induced by interleukin-1beta in rat vascular smooth muscle cells. J Pharmacol Exp Ther 325:200-9
Veerappan, Arul; Reid, Alicia C; Estephan, Racha et al. (2008) Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction. Proc Natl Acad Sci U S A 105:1315-20
Kano, Seiichiro; Tyler, Eleanor; Salazar-Rodriguez, Mariselis et al. (2008) Immediate hypersensitivity elicits renin release from cardiac mast cells. Int Arch Allergy Immunol 146:71-5
Levi, Roberto; Seyedi, Nahid; Schaefer, Ulrich et al. (2007) Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway. Biochem Pharmacol 73:1146-56

Showing the most recent 10 out of 16 publications