Abstract
BackgroundT89, 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.MethodsMale 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.ResultsT89 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.ConclusionT89 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.
Highlights
Cardiovascular events due to ischemic heart disease contribute to the majority of deaths among cardiovascular disorders worldwide (Katz and Gavin, 2019)
We first confirmed that treatment with T89 notably elevated ISO-induced low survival rate of rats and improved cardiac injury, mainly manifesting as alleviation of cardiac hypertrophy, preservation of myocardial morphology, and ultrastructure, resulting in restoration of MBF and heart function
The regulation of metabolism and recovery of mitochondrial function by T89 may be the underlying mechanism contributing to the potential effect of T89 on ISOelicited cardiac injury
Summary
Cardiovascular events due to ischemic heart disease contribute to the majority of deaths among cardiovascular disorders worldwide (Katz and Gavin, 2019). It has been well evidenced that ISO-induced cardiac injury implicates metabolism disorders, involving abnormalities in glycolipid metabolism and energy metabolism (Stapel et al, 2017). ISO has been demonstrated to induce mitochondrial oxidative phosphorylation impairment (Krestinina et al, 2020), which in turn, along with glycolipid disorders, resulted in reduction of ATP production. Electrons produced by the oxidation of NADH or succinate by Complex I or II, respectively, are transferred to complex III via the pool of ubiquinone and to complex IV (cytochrome c oxidase) via soluble cytochrome c (Guo et al, 2017). The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury
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