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.
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.
|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