Cardiac hypertrophy is the heart's compensatory response to a variety of extrinsic and intrinsic stimuli. Cardiac hypertrophy is believed to have a compensatory function by diminishing wall stress. Yet, paradoxically, ventricular hypertrophy is associated with a significant increase in the risk of heart failure and malignant arrhythmia. Inhibition of the nuclear factor, NF-?B, has recently been investigated as one of the possible therapeutic approaches to the treatment of cardiac hypertrophy and the results, and clinical significance promise to be vast. We surmised that the use of soluble inhibitors of NF-?B would present an attractive therapeutic means to treat cardiac hypertrophy. On the other hand, NF-?B can be both anti- and pro-apoptotic in certain conditions. Therefore, the beneficial effects of NF-?B inhibitors in cardiac hypertrophy remain to be systematically investigated. Motivated by the uncertainties, and the therapeutic potential of the inhibitors of this nuclear factor, we have obtained surprising yet, exciting data which demonstrate the beneficial effects of several novel potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. In addition, EETs inhibit the activation of NF-?B-mediated gene transcription. Specifically, we have shown that there is an almost complete resolution of cardiac hypertrophy by sEH inhibitors independent of the antihypertensive effects. We were able to demonstrate in our preliminary findings that these compounds potently block the NF-?B activation in cardiac myocytes. Moreover, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias which occur in association with cardiac hypertrophy. Inspired by these initial observations, we reason that these compounds can be exploited to be used as a tool to systematically probe the possible beneficial effects of sEH inhibition in the short- and long-term treatment of cardiac hypertrophy as well as to study the mechanisms and involvement of NF-?B signaling pathway in cardiac hypertrophy. Thus, the central goal of the proposal is to use sEH inhibitors to directly test the novel concept that enhancement of endogenous EETs can be used as a mean to prevent and reverse cardiac hypertrophy and prevent the occurrence of cardiac arrhythmias via inhibition of NF-?B activation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-F (02))
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Awasthi, Samir; Izu, Leighton T; Mao, Ziliang et al. (2016) Multimodal SHG-2PF Imaging of Microdomain Ca2+-Contraction Coupling in Live Cardiac Myocytes. Circ Res 118:e19-28
Sihn, Choong-Ryoul; Kim, Hyo Jeong; Woltz, Ryan L et al. (2016) Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. J Biol Chem 291:2499-509
Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:
Lu, Ling; Sirish, Padmini; Zhang, Zheng et al. (2015) Regulation of gene transcription by voltage-gated L-type calcium channel, Cav1.3. J Biol Chem 290:4663-76
Zhang, Xiao-Dong; Lieu, Deborah K; Chiamvimonvat, Nipavan (2015) Small-conductance Ca2+ -activated K+ channels and cardiac arrhythmias. Heart Rhythm 12:1845-51
Myers, Richard; Timofeyev, Valeriy; Li, Ning et al. (2015) Feedback mechanisms for cardiac-specific microRNAs and cAMP signaling in electrical remodeling. Circ Arrhythm Electrophysiol 8:942-50
Wang, Wenying; Flores, Maria Cristina Perez; Sihn, Choong-Ryoul et al. (2015) Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions. J Gen Physiol 145:201-12
Zhang, Xiao-Dong; Lee, Jeong-Han; Lv, Ping et al. (2015) Etiology of distinct membrane excitability in pre- and posthearing auditory neurons relies on activity of Cl- channel TMEM16A. Proc Natl Acad Sci U S A 112:2575-80
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
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:

Showing the most recent 10 out of 57 publications