Author + information
- SangJin Kim,
- Xiao Lei Gao,
- Sun Hwa Lee,
- LaeYoung Jung,
- YiShik Kim,
- Hae-Eun Yun,
- SangRok Lee,
- WonHo Kim,
- JaeKi Ko and
- JeiKeon Chae
Endothelial dysfunction in diabetes results in impaired synthesis of vasoactive substances, whereas the mechanisms responsible for diabetic vascular dysfunction remain poorly understood. Studies have shown that epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 (CYPs) have been considered as endothelium-derived hyperpolarizing factors (EDHFs). Calpain, Ca2+-dependent enzymes, selectively cleaves a specific subset of cellular proteins, including cytoskeletal and membrane proteins, and transcription factors. Studies have shown that calpain induces the degradation of RXRα and prevents PPARα, a key regulator of CYP2J3, from heterodimer formation and gene transcription. However, the relationship between calpain and CYP epoxygenase are not elucidated yet in diabetic endothelial dysfunction.
PPAR-αagonist, fenofibrate, was treated in ob-/ob- rats for 2 weeks and the expression of calpain, RXRα, PPAR-αand CYP2J3 were assessed by western blotting and RT-PCR in hearts, aortas and H9C2 cells. Acetylcholine (ACh) and 11,12-EET-induced vasolaxation was measured in ob-/ob- rat thoracic aortic ring. 11,12-EET was measured by LC/MS.
Calpain expression was up-regulated and RXRα, PPAR-αexpression were down-regulated leading to decrease of CYP2J3 expression and 11,12-EETs level in diabetic ob-/ob- rat hearts. ACh and 11,12-EET-induced vasorelaxation were markedly decreased in ob-/ob- rat aortic rings. Administration of fenofibrate reduced calpain activity and restored expression of RXRα, PPAR-αand CYP2J3. Concurrently, ACh- and 11,12-EET-induced vasorelaxation were also recovered by fenofibrate corresponding to the enhanced CYP2J3 expression and 11,12-EET level. H2O2 provoked Ca2+ overload and increase of calpain activity, followed by proteolysis of RXRα and decreased of PPAR-αand CYP2J2 with time-dependent manner in BAECs.
Calpain induces proteolysis of RXRα,thus inhibits RXRα and PPAR-αheterodimer formation resulting in the suppressed CYP2J3 expression. The increased activity of calpain and reduced synthesis of 11,12-EETs may contribute to endothelial and cardiovascular dysfunction in diabetic ob-/ob- rats.
Poster Sessions, Expo North
Sunday, March 10, 2013, 9:45 a.m.-10:30 a.m.
Session Title: New Insights into Heart Failure Pathophysiology
Abstract Category: 16. Heart Failure: Basic
Presentation Number: 1222-296
- 2013 American College of Cardiology Foundation