Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies

Abstract

Schizandrol A (SA) is an bioactive component isolated from the Schisandra chinensis (Turcz.) Baill., which has been used as a remedy to prevent oxidative injury. However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. AMI was induced in ICR mice by coronary artery ligation, then SA (6 mg·kg −1 ·d −1 , ip) was administered. SA treatment significantly decreased the infarct size, preserved the cardiac function, and improved the biochemical indicators and cardiac pathological alterations. Moreover, SA (10, 100 M) significantly decreased the apoptotic index in OGD-treated H8c2 cardiomycytes in vitro. By using HPLC-Q-TOF/MS, we conducted metabonomics analysis to screen the significantly changed endogenous metabolites and construct the network in both serum and urine. The results revealed that SA regulated the pathways of glycine, serine and threonine metabolism, lysine biosynthesis, pyrimidine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, valine, leucine and isoleucine biosynthesis under the pathological conditions of AMI. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5’-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. In addition, SA was found to facilitate PI3K/Akt activation and inhibit the expression of NOX2 in AMI mice and OGD-treated H9c2 cells. In conclusion, we have elucidated SA-regulated endogenous metabolic pathways and constructed a regulatory metabolic network map. Furthermore, we have validated the new potential therapeutic targets and underlying molecular mechanisms of SA against AMI, which might provide a reference for its future application in cardiovascular diseases.

Cardioprotective effect of ginsenoside Rb1 via regulating metabolomics profiling and AMP-activated protein kinase-dependent mitophagy

“…The functional metabolomics found that N-acetylneuraminic acid was a potential metabolic marker for CAD progression and silencing its regulatory enzyme, neuraminidase-1, might become an unrecognized therapeutic intervention for CAD [ 15 ]. In our previous study, schizandrol A effectively protected AMI mice through upregulation of ecto-5′-nucleotidase, methionine synthase and platelet-derived endothelial cell growth factor based on metabolomics analysis [ 16 ].…”

Virtual screening and network pharmacology-based synergistic mechanism identification of multiple components contained in Guanxin V against coronary artery disease

“…Schizandra Chinensis Fructus extracts induce apoptosis via the ROS-mediated/mitochondriadependent pathway and JNK/p38 MAPK activation [89]. In addition, Schizandra Chinensis Fructus was found to facilitate PI3K-AKT activation and inhibit the expression of NOX2 in AMI mice and oxygen-glucose deprivationtreated H9c2 cells [90]. Rehmannia Radix Praeparata had efficient detectable antioxidant activity [91], and the PI3K-Akt and MAPK signaling pathways were found in the pathway analysis for CAD on Rehmannia Radix Praeparata [92].…”

Effect of Acute High-Intensity Exercise on Rat Myocardium metabolic Profiles. An LC-MS Based Metabolomics Study

“…Laitano's research showed during the recovery period after high-intensity running wheel training, the level of uracil in the myocardium of mice was signi cantly increased, which was essential for myocardial repair after strenuous exercise [36] . Study showed the plasma thymine in mice with acute myocardial ischemia increased signi cantly and the expansion of thymine was closely related to the risk of heart disease [37] . Peng's research showed a signi cant decrease in thymidine in rats' serum can be used as a biomarker of early acute myocardial infarction [38] .…”