Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis.
BACKGROUND
Recent studies have reported that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) can improve angiogenesis. Using an acute infarction model, we examined the therapeutic merit of statins on angiogenesis, alone and in combination with cell-based therapy.


METHODS
Zucker fatty rats, a strain characterized by obesity, hyperglycemia, and hyperlipidemia, were used for this study. After ligating the left anterior descending artery, rats were given oral pravastatin 5 or 50 mg/kg per day, or an intramyocardial injection of a total 2 x 10(7) autologous bone marrow mononuclear cells, or a combination of both. Cardiac function was assessed by echocardiography before treatment, then 7, 14, and 28 days after treatment. Histologic estimation of microvessel density, lymphocyte infiltration, and collagen fiber accumulation in the infarcted myocardium was performed 28 days after treatment.


RESULTS
Cardiac function was improved, and collagen deposition was decreased significantly after either cell implantation or pravastatin administration alone, but no synergistic effect was seen by their combination. However, microvessel density in the infarcted myocardium was increased only by implantation of bone marrow mononuclear cells, and not by administration of pravastatin. Pravastatin resulted in significant decreases in the serum levels of interleukin 1beta and tumor necrosis factor-alpha, and also in the infiltration of CD45-positive cells, but not CD117-positive stem cells, in infarcted myocardium. Neither the number of circulating CD34-positive cells nor their endothelial differentiation potency was increased significantly 14 days after oral administration of pravastatin.


CONCLUSIONS
Pravastatin can improve cardiac function after myocardial infarction, but through an antiinflammatory mechanism, rather than by induction of therapeutic angiogenesis. No synergistic effect for inducing angiogenesis was found by the combination of pravastatin and implantation of bone marrow mononuclear cells.
Li
Tao-Sheng
TS
Division of Cardiovascular Surgery, Department of Medical Bioregulation, Yamaguchi University School of Medicine, Yamaguchi, Japan. litaoshe@yamaguchi-u.ac.jp
Takahashi
Masaya
M
Suzuki
Ryo
R
Kobayashi
Toshiro
T
Ito
Hiroshi
H
Mikamo
Akihito
A
Hamano
Kimikazu
K
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000032:analysis; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007267:Injections; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D016037:Single-Blind Method; D014280:Triglycerides / Q000097:blood; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D014280:Triglycerides; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D017035:Pravastatin