Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy.
OBJECTIVE
Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterol-lowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy.


METHODS
Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-alpha, IL-1beta, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/macrophage antigen alpha, CD18/beta2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferase-p21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot.


RESULTS
Diabetes was associated with induced cardiac stainings of TNF-alpha, IL-1beta, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetes-induced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p < 0.05) and 3.2-fold (p < 0.0005), respectively, and normalised the reduced eNOS production caused by diabetes.


CONCLUSIONS
These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.
Van Linthout
S
S
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Riad
A
A
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Dhayat
N
N
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Spillmann
F
F
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Du
J
J
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Dhayat
S
S
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Westermann
D
D
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Hilfiker-Kleiner
D
D
Department of Cardiology, Medical School Hannover, Hannover, Germany.
Noutsias
M
M
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Laufs
U
U
Department of Cardiology, University of Saarland, Homburg/Saar, Germany.
Schultheiss
H-P
HP
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Tschöpe
C
C
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. ctschoepe@yahoo.com.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D003094:Collagen; D000069059:Atorvastatin