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. 2021 Apr 22;13(8):11954-11968.
doi: 10.18632/aging.202898. Epub 2021 Apr 22.

Influence of atorvastatin on metabolic pattern of rats with pulmonary hypertension

Li Luo  1   2 , Jianmin Wu  1 , Taijie Lin  2 , Guili Lian  2 , Huajun Wang  2 , Gufeng Gao  3 , Liangdi Xie  1   2
Affiliations

Influence of atorvastatin on metabolic pattern of rats with pulmonary hypertension

Li Luo et al. Aging (Albany NY). .

Abstract

Background: Metabonomics has been widely used to analyze the initiation, progress, and development of diseases. However, application of metabonomics to explore the mechanism of pulmonary arterial hypertension (PAH) are poorly reported. This study aimed to investigate the influence of atorvastatin (Ato) on metabolic pattern of rats with pulmonary hypertension.

Methods: PAH animal model was established using monocrotaline (MCT). The mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were measured. The microstructure of pulmonary arterioles was observed by HE staining. Nuclear magnetic resonance was used to detect and analyze the serum metabolites. The levels of glycogen synthase kinase-3β (GSK-3β), hexokinase 2 (HK-2), sterol regulatory element-binding protein 1c (SREBP-1c), and carnitine palmitoyltransferase I (CPT-1) in the lung tissues were measured.

Results: Ato significantly improved lung function by decreasing mPAP, RVHI, wall thickness, and wall area. Differences in metabolic patterns were observed among normal, PAH, and Ato group. The levels of GSK-3β and SREBP-1c were decreased, but HK-2 and CPT-1 were increased in the group PAH. Ato treatment markedly reversed the influence of MCT.

Conclusion: Ato significantly improved the pulmonary vascular remodeling and pulmonary hypertension of PAH rats due to its inhibition on Warburg effect and fatty acid β oxidation.

Keywords: Warburg effect; fatty acid β oxidation; metabonomics; monocrotaline; pulmonary arterial hypertension.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Ato improved the lung function of PAH rats. (A) Pathological changes of lung tissues after treatment with MCT and Ato; (B) mPAP of rats in different groups was measured at different time points; (C) RVHI of rats in different groups was measured at different time points; (D) WT was measured at different time points after treatment with MCT and Ato; (E) WA was measured at different time points after treatment with MCT and Ato. (*P<0.05, compared with control group, #P<0.05, compared with group PAH). Ten rats were used in each group.
Figure 2
Figure 2
PLS-DA analysis was used to investigate the influence of Ato on the metabonomics of PAH rats. (A) The serum metabolic patterns of rats in different groups can be distinguished; (B) The metabonomics differences between group control and Ato (1 week) could be distinguished; (C) The metabonomics differences between group Ato (1 week) and Ato (2-3 week) could be distinguished; (D) The metabonomics differences between group Ato (2-3 week) and Ato (4 week) could be distinguished.
Figure 3
Figure 3
OPLS-DA analysis was used to find differential metabolites between different groups. (A) Differential metabolites were investigated between group control and Ato (1 week); (B) Differential metabolites were investigated between group Ato (1 week) and Ato (2-3 week); (C) Differential metabolites were investigated between group Ato (2-3 week) and Ato (4 week).
Figure 4
Figure 4
Influence of Ato on the mRNA expression of GSK-3β, HK-2, SREBP-1c, and CPT-1 in the lung tissues. (A) The mRNA level of GSK-3β was detected after treatment with MCT and Ato; (B) The mRNA level of HK-2 was detected after treatment with MCT and Ato; (C) The mRNA level of SREBP-1c was detected after treatment with MCT and Ato; (D) The mRNA level of CPT-1 was detected after treatment with MCT and Ato. (*P<0.05, compared with control group, #P<0.05, compared with group PAH).
Figure 5
Figure 5
The protein expression changes of GSK-3β, HK-2, SREBP-1c, and CPT-1 in the group PAH. (A) The protein levels in the lung tissues of PAH rats was measured using western blotting; (B) The protein expression change of GSK-3β was quantified; (C) The protein expression of p-GSK-3β was quantified; (D) The protein expression of HK-2 in the lung tissues was quantified; (E) The protein expression of SREBP-1c was quantified; (F) The protein expression of CPT-1 was quantified. (*P<0.05, compared with control group).
Figure 6
Figure 6
Influence of Ato on the protein levels of GSK-3β, HK-2, SERBP-1c, and CPT-1 in the lung tissues. (A) The protein levels in the lung tissues of Ato treated rats was measured using western blotting; (B) The protein expression was quantified.
Figure 7
Figure 7
A schematic image for how Ato improve lung function of PAH rats.
See this image and copyright information in PMC

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