Submitted on January 10, 2008
Revised on April 22, 2008
Accepted on April 25, 2008
Calcineurin Is Critical for Sodium-Induced Neointimal Formation in Normotensive And Hypertensive Rats
Ryo Takeda1, Etsu Suzuki2*, Masao Takahashi1, Shigeyoshi Oba3, Hiroaki Nishimatsu3, Kenjiro Kimura2, Tetsuo Nagano3, Ryozo Nagai3, and Yasunobu Hirata
1 Univ. of Tokyo
2 St. Marianna University School of Medicine
3 Univ. of Toky
* To whom correspondence should be addressed. E-mail: esuzuki-tky{at}umin.ac.jp.
It is well known that an excessive intake of sodium chloride (sodium) is a risk factor for cardiovascular disease because it raises the blood pressure. However, sodium loading reportedly promotes cardiovascular disease independently of its effect on blood pressure. To examine the mechanisms by which sodium loading promotes vascular inflammation independently of its effect on blood pressure, we examined the role of calcineurin in sodium loading-induced vascular inflammation using a wire injury model of the rat femoral artery. Calcineurin mRNA expression in the wire-injured femoral artery was significantly higher in sodium-loaded normotensive rats such as Wistar Kyoto (WKY) rats than that in control WKY rats. Neointimal formation was also significantly enhanced in sodium-loaded WKY rats as compared with control WKY rats. Gene transfer of an adenovirus expressing a dominant-negative mutant of calcineurin (AdCalA
C92Q) significantly suppressed neointimal formation in sodium-loaded WKY rats to a level similar to that observed in control WKY rats. Calcineurin expression and neointimal formation were more significantly enhanced in hypertensive rats, such as spontaneously hypertensive rats (SHR) than those in control WKY rats. AdCalAC92Q infection significantly suppressed neointimal formation in SHR to a level similar to that observed in control WKY rats. These results suggest that sodium loading promotes neointimal formation, even in normotensive rats, and that hypertension further stimulates neointimal formation. These results also suggest that calcineurin plays a pivotal role in this process.
