Abstract
Targeting Nrf2 signaling appears to be an attractive approach for the treatment of maladaptive cardiac remodeling and dysfunction; however, pharmacological modulation of the Nrf2 pathway in the cardiovascular system remains to be established. Herein, we report that a novel synthetic triterpenoid derivative, dihydro-CDDO-trifluoroethyl amide (dh404), activates Nrf2 and suppresses oxidative stress in cardiomyocytes. Dh404 interrupted the Keap1-Cul3-Rbx1 E3 ligase complex-mediated Nrf2 ubiquitination and subsequent degradation saturating the binding capacity of Keap1 to Nrf2, thereby rendering more Nrf2 to be translocated into the nuclei to activate Nrf2-driven gene transcription. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 was resistant to dh404-induced stabilization of Nrf2 protein. In addition, dh404 did not dissociate the interaction of Nrf2 with the Keap1-Cul3-Rbx1 E3 ligase complex. Thus, it is likely that dh404 inhibits the ability of Keap1-Cul3-Rbx1 E3 ligase complex to target Nrf2 for ubiquitination and degradation via modifying Cys-151 of Keap1 to change the conformation of the complex. Moreover, dh404 was able to stabilize Nrf2 protein, to enhance Nrf2 nuclear translocation, to activate Nrf2-driven transcription, and to suppress angiotensin II (Ang II)-induced oxidative stress in cardiomyocytes. Knockdown of Nrf2 almost blocked the anti-oxidative effect of dh404. Dh404 activated Nrf2 signaling in the heart. Taken together, dh404 appears to be a novel Nrf2 activator with a therapeutic potential for cardiac diseases via suppressing oxidative stress.
Highlights
Triterpenoids, synthesized in many plants, including a large variety of vegetarian foods and medicinal herbs, are widely used as traditional medicine of in Asian countries [1]
It has been well documented that synthetic triterpenoid derivatives are able to activate Nrf2 [4], we synthesized a novel triterpenoid derivative of dihydro-CDDO-trifluoroethyl amide that was named dh404 (Figure 1) and investigated the impact of dh404 on Keap1-Nrf2 homeostasis
We have previously demonstrated that C273 and C288 which are distinct cysteine residues in Keap1, are required for Keap1-mediated constitutive suppression of Nrf2 activity, and C151, that is required for escape by Nrf2 from Keap1-dependent suppression in response to sulforaphane and oxidative stress [26]
Summary
Triterpenoids, synthesized in many plants, including a large variety of vegetarian foods and medicinal herbs, are widely used as traditional medicine of in Asian countries [1]. To improve the pharmacological potency, novel derivatives of OA, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien28-oic acid (CDDO), CDDO methyl ester (CDDO-Me), CDDO imidazolides (CDDO-Im), and CDDO amides (methyl amide, CDDO-MA; ethyl amide, CDDO-EA), have been synthesized [3]. These synthetic derivatives of OA are potent multifunctional molecules in vitro. They can suppress inflammation, activate cytoprotective pathways, induce differentiation, inhibit proliferation and induce apoptosis. They are the most potent anti-inflammatory and anti-carcinogenic triterpenoinds identified [4]. The therapeutic potential of synthetic oleanane triterpenoids (SO) in cardiovascular diseases has not been explored
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