期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 49, 页码 18733-18738出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0609158103
关键词
epoxyeicosatrienoic acids; NF-kappa B
资金
- NHLBI NIH HHS [R01 HL085844, R01 HL068507, R01 HL085727, HL 68507, HL 67737] Funding Source: Medline
- NIEHS NIH HHS [R01 ES011634, P30 ES 05707, P42 ES004699, R37 ES 02710, P30 ES005707, P42 ES 04699, ES 11634, R37 ES002710] Funding Source: Medline
Sustained cardiac hypertrophy represents one of the most common causes leading to cardiac failure. There is emerging evidence to implicate the involvement of NF-kappa B in the development of cardiac hypertrophy. However, several critical questions remain unanswered. We tested the use of soluble epoxide hydrolase (sEH) inhibitors as a means to enhance the biological activities of epoxyeicosatrienoic acids (EETs) to treat cardiac hypertrophy. sEH catalyzes the conversion of EETs to form the corresponding dihydroxyeicosatrienoic acids. Previous data have suggested that EETs may inhibit the activation of NF-kappa B-mediated gene transcription. We directly demonstrate the beneficial effects of several potent sEH inhibitors (sEHIs) in cardiac hypertrophy. Specifically, we show that sEHIs can prevent the development of cardiac hypertrophy using a murine model of pressure-induced cardiac hypertrophy. in addition, sEHIs reverse the preestablished cardiac hypertrophy caused by chronic pressure overload. We further demonstrate that these compounds potently block the NF-kappa B activation in cardiac myocytes. Moreover, by using in vivo electro-physiologic recordings, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias that occur in association with cardiac hypertrophy. We conclude that the use of sEHIs to increase the level of the endogenous lipid epoxides such as EETs may represent a viable and completely unexplored avenue to reduce cardiac hypertrophy by blocking NF-kappa B activation.
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