Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Sustained cardiac hypertrophy represents one of the most common causes leading to heart failure. Once heart failure develops, the condition is irreversible and is associated with a very high mortality rate. Moreover, cardiac hypertrophy and failure are associated with an increase in both atrial and ventricular arrhythmias and sudden cardiac death. During our last funding cycle, we have demonstrated the beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and MI models. Our preliminary findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. These results are exciting because they demonstrate for the first time a broader salutary effects in cardiac remodeling (not limited to just myocyte hypertrophy) of this novel class of compounds. Thus, the central objective of this competing renewal is to test the beneficial effects of sEHIs in cardiac remodeling by modifying cardiac fibrosis. Additionally, since atrial fibrosis plays a central role in atrial fibrillation (AF), we urther propose that sEH may represent a new therapeutic target for the treatment of AF. Indeed, AF represents one the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality. Hence, new treatment paradigms for AF are likely to be highly impactful.

Public Health Relevance

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Both cardiac hypertrophy and heart failure are associated with an increase in atrial and ventricular arrhythmias and sudden cardiac death. Hence, new treatment paradigms to target progressive cardiac remodeling are likely to be of high impact clinically.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL085727-05A1
Application #
8449852
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2006-07-01
Project End
2017-02-28
Budget Start
2013-06-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$366,520
Indirect Cost
$128,520
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Rafizadeh, Sassan; Zhang, Zheng; Woltz, Ryan L et al. (2014) Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel. Proc Natl Acad Sci U S A 111:9989-94
Wang, Wenying; Kim, Hyo Jeong; Lee, Jeong-Han et al. (2014) Functional significance of K+ channel ?-subunit KCNE3 in auditory neurons. J Biol Chem 289:16802-13
Despa, Sanda; Sharma, Savita; Harris, Todd R et al. (2014) Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. J Am Heart Assoc 3:
Lv, Ping; Kim, Hyo Jeong; Lee, Jeong-Han et al. (2014) Genetic, cellular, and functional evidence for Ca2+ inflow through Cav1.2 and Cav1.3 channels in murine spiral ganglion neurons. J Neurosci 34:7383-93
Jian, Zhong; Han, Huilan; Zhang, Tieqiao et al. (2014) Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling. Sci Signal 7:ra27
Zhang, Xiao-Dong; Timofeyev, Valeriy; Li, Ning et al. (2014) Critical roles of a small conductance Caýýýýý-activated Kýýý channel (SK3) in the repolarization process of atrial myocytes. Cardiovasc Res 101:317-25
Sirish, Padmini; Li, Ning; Liu, Jun-Yan et al. (2013) Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis. Proc Natl Acad Sci U S A 110:5618-23
Ulu, Arzu; Harris, Todd R; Morisseau, Christophe et al. (2013) Anti-inflammatory effects of ?-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J Cardiovasc Pharmacol 62:285-97
Lieu, Deborah K; Fu, Ji-Dong; Chiamvimonvat, Nipavan et al. (2013) Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol 6:191-201
Xu, Dan-yan; Davis, Benjamin B; Wang, Zhen-he et al. (2013) A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPAR? to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction. Int J Cardiol 167:1298-304

Showing the most recent 10 out of 35 publications