Abstract
Notoginseng (Sanqi), the roots and rhizomes of Panax notoginseng and safflower, the flowers of Carthamus tinctorius, are widely used traditional Chinese medicines (TCMs) for the treatment of cardiovascular diseases. Positive evidences have fueled growing acceptance for cardioprotective effects of the combination of the notoginseng total saponins and safflower total flavonoids (CNS) against myocardial ischemia (MI). However, the underlying cardioprotective mechanisms of CNS are still obscured. Metabolomics is a comprehensive tool for investigating biological mechanisms of disease, monitoring therapeutic outcomes, and advancing drug discovery and development. Herein, we investigated the cardioprotective effects of CNS on the isoproterenol (ISO)-induced MI rats by using plasma and urine metabolomics based on ultra-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) and multiple pharmacodynamics approaches. The results showed that pretreatment with CNS could attenuate the cardiac injury resulting from ISO, as evidenced by decreasing the myocardial infarct size, converting the echocardiographic, histopathological, and plasma biochemical abnormalities, and reversing the perturbations of plasma and urine metabolic profiles, particularly for the 55.0 mg/kg dosage group. In addition, 44 metabolites were identified as the potential MI biomarkers, mainly including a range of free fatty acids (FFAs), sphingolipids, and glycerophospholipids. CNS pretreatment group may robustly ameliorate these potential MI-related biomarkers. The accumulation of LysoPCs and FFAs, caused by PLA2, may activate NF-κB pathway and increase proinflammatory cytokines. However, our results showed that CNS at 55.0 mg/kg dosage could maximally attenuate the NF-κB signaling pathway, depress the expressions of TNF-α, IL-6, IL-1β, and PLA2. The results suggested that the anti-inflammatory property of CNS may contribute to its cardioprotection against MI. Our results demonstrate that the integrating of metabolomics with pharmacodynamics provides a reasonable approach for understanding the therapeutic effects of TCMs and CNS provide a potential candidate for prevention and treatment of MI.
Highlights
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide and myocardial ischemia (MI) is the most predominant presentation of CVDs (Dominguez-Rodriguez et al, 2014)
With the advent and development of metabolomic platform, metabolomics has been shown to be a highly specific and useful tool for the diagnosis of disease and evaluation of drug efficacy, which resulted a considerable process in the definition of MI and drug discovery and development
Of particular note was that the pretreatment with middle dose of CNS (M-CNS) substantially attenuated the elevation of ST-segments in ECG, lowered the plasma levels of cardiac troponin T (cTnT), creatine kinase (CK), and lactate dehydrogenase (LDH), and inhibited the histopathological damages in MI rats
Summary
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide and MI is the most predominant presentation of CVDs (Dominguez-Rodriguez et al, 2014). The experimental model of ISO-induced MI offered a reliable technique to investigate the efficacy of various potentially cardioprotective agents, which has been frequently documented in previous studies (Fathiazad et al, 2012). TCM has been accepted worldwide as a powerful alternative for acute or chronic disorders. CDDP, a commonly used TCM patent drug to treat CVDs in China has been approved by Food and Drug Administration (FDA) of United States for stages II and III Investigational New Drug (IND) examinations (Sun et al, 2013; Luo et al, 2015)
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