Atorvastatin prevents dehydromonocrotaline-induced pulmonary hypertension in beagles.
BACKGROUND
Pulmonary arterial hypertension is a life-threatening disease characterized by marked and sustained elevation of blood pressure in the lungs. Statins, 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, have been shown to attenuate the effects of pulmonary hypertension resulting from hypoxia, Monocrotaline exposure, or Monocrotaline exposure in the setting of pneumonectomy. In particular, the effects of Simvastatin have been well studied. Whether other statins, such as Atorvastatin, are capable of preventing dehydromonocrotaline-induced pulmonary hypertension in beagles has not been explored.


METHODS
We used eighteen 3-month-old beagles of both genders, weighing 10.3 ± 3.2 kg. The experimental animals were randomized into one of 3 groups: the control group (n = 6), the dehydromonocrotaline (DHMC) + vehicle group (n = 5), and the DHMC + Atorvastatin group (n = 7). The beagles were injected with DHMC (n = 12) on day 1, and from day 5 to day 65 they received Atorvastatin (2 mg/kg, daily by gavage) or vehicle (0.9% saline, daily by gavage) treatment. We used the thermodilution method of hemodynamic measurements at baseline and at day 65 of treatment. At day 65, pulmonary tissue was sampled for morphometry and real-time quantitative PCR.


RESULTS
After 65 days, DHMC increased mean pulmonary arterial pressure (mPAP), and this increase was prevented with Atorvastatin treatment (32 ± 11 mmHg vs. 15 ± 3 mmHg, P < .05). Hematoxylin and eosin staining demonstrated less pulmonary endothelium destruction and smooth muscle cell proliferation in the Atorvastatin-treated beagles, compared with the DHMC group. The eNOS mRNA expression was increased in the DHMC group, and this increase was prevented in the Atorvastatin-treated group. In addition, IL-1β, prepro-ET-1, TNF-α, and VEGF (vascular endothelial growth factor) mRNA expression levels were increased in the lungs of the DHMC group, and these increases were reduced toward normal levels in the Atorvastatin-treated group.


CONCLUSIONS
Atorvastatin prevents the effects of monocrotaline-induced pulmonary hypertension in beagles.
Department of Cardiology, Zhongshan Hospital of Fudan University, Shanghai Cardiovascular Disease Institute,   Shanghai,   China.
Dandan
D
Chen
Daxin
D
Zhou
Juying
J
Qian
Fadong
F
Chen
Lihua
L
Guan
Lili
L
Dong
Junbo
J
Ge
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D011758:Pyrroles / Q000627:therapeutic use*
D000477:Alkylating Agents; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III