Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

Xiao-Hong Wei; Xiao Guo; Chun-Shui Pan; Huan Li; Yuan-Chen Cui; Li Yan; Jing-Yu Fan; Jing-Na Deng; Bai-He Hu; Xin Chang; Shu-Ya He; Lu-Lu Yan; Kai Sun; Chuan-She Wang; Jing-Yan Han

doi:10.3389/fphys.2021.653349

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T₈₉ on Isoproterenol-Induced Cardiac Injury

Front Physiol. 2021 Jun 28:12:653349. doi: 10.3389/fphys.2021.653349. eCollection 2021.

Authors

Xiao-Hong Wei^{1

2

3

4

5

6}, Xiao Guo^{1

2

3

4

5

6}, Chun-Shui Pan^{2

3

4

5

6}, Huan Li^{1

2

3

4

5

6}, Yuan-Chen Cui^{2

3

4

5

6}, Li Yan^{2

3

4

5

6}, Jing-Yu Fan^{2

5

6}, Jing-Na Deng^{2

3

4

5

6}, Bai-He Hu^{2

3

4

5

6}, Xin Chang^{2

3

4

5

6}, Shu-Ya He^{1

2

3

4

5

6}, Lu-Lu Yan^{2

3

4

5

6}, Kai Sun^{2

3

4

5

6}, Chuan-She Wang^{1

2

3

4

5

6}, Jing-Yan Han^{1

2

3

4

5

6}

Affiliations

¹ Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
² Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.
³ Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, China.
⁴ Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine, Beijing, China.
⁵ Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine, Beijing, China.
⁶ State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, China.

Abstract

Background: T₈₉, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T₈₉ on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T₈₉ on ISO-induced cardiac injury.

Methods: Male Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T₈₉ at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed.

Results: T₈₉ obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T₈₉ relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T₈₉ inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T₈₉ significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T₈₉ in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641.

Conclusion: T₈₉ reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T₈₉ is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

Keywords: cardiac hypertrophy; energy metabolism; fatty acid oxidation; glycolysis; mitochondrial electron transport chain.