HMG-CoA reductase inhibitor cerivastatin prolonged rat cardiac allograft survival by blocking intercellular signals.
BACKGROUND
The development of atherosclerotic cardiovascular complications caused by hyperlipidemia is a common and serious problem for long-term survivors of organ transplantation. However, adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and lymphocyte function-associated antigen (LFA)-1 are involved in allograft rejection, possibly by providing costimulatory signals. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin has been shown to suppress ICAM-1 expression in acute inflammatory responses.


METHODS
In this study, we evaluated the immunosuppressive effects of cerivastatin in rat cardiac allografts. The hearts of Fischer rats were transplanted heterotopically into Lewis rats. Cerivastatin (2 mg/kg) was administrated intraperitoneally to recipients for 7 consecutive days from the day before transplantation.


RESULTS
Graft survival in the cerivastatin-treated group (n = 8) was significantly longer than in controls (n = 10) (24.6 +/- 2.2 days vs 10.2 +/- 1.3 days, p < 0.05). Mixed lymphocyte reaction (MLR) showed that on Day 8 after grafting, the proliferative response of alloreactive T cells against F344 alloantigen in cerivastatin-treated rats was significantly more suppressed than in Lewis rats. The Interleukin-2 concentration of supernatant in MLR cultures in the cerivastatin-treated group was lower than in the control group. Immunohistochemical analysis showed that the percentage of CD4-positive cells to infiltrating mononuclear cells was less prominent in the cerivastatin-treated group (9.8% +/- 2.2%) than in the control group (20.9% +/- 3.2%).


CONCLUSIONS
The HMG-CoA reductase inhibitor cerivastatin effectively suppressed acute graft rejection, possibly by blocking intercellular signals via ICAM/LFA-1, and cerivastatin may be a candidate for treating patients with hyperlipidemia who undergo organ transplantation.
Horimoto
Hitoshi
H
Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, Takatsuki, Japan. tho043@poh.osaka-med.ac.jp
Nakai
Yasunari
Y
Nakahara
Ken ich
Ki
Nomura
Yukiya
Y
Mieno
Shigetoshi
S
Sasaki
Shinjiro
S
D000818:Animals; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D011725:Pyridines; D018799:Intercellular Adhesion Molecule-1; C086276:cerivastatin