2. Academic Validation
  3. Salvianolic acid B drives gluconeogenesis and peroxisomal redox remodeling in cardiac ischemia/reperfusion injury: A metabolism regulation by metabolite signal crosstalk

Salvianolic acid B drives gluconeogenesis and peroxisomal redox remodeling in cardiac ischemia/reperfusion injury: A metabolism regulation by metabolite signal crosstalk

  • Free Radic Biol Med. 2025 Mar 1:229:399-414. doi: 10.1016/j.freeradbiomed.2025.01.037.
Jin-Shan Li 1,  Xiao-Ming Qi 2,  Qing-Fang Li 3,  Wei-Wei Wu 4,  Yuan-Lin Zhang 5,  Hai-Xin Liu 6,  Jin-Hong Ren 7,  Jun-Yan Liu 8,  Ji-Hui Lin 9,  Qi-Yan Wang 10,  Yuan-Biao Qiao 11,  Qing-Shan Li 12
Affiliations

Affiliations

  • 1 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: 15035293454@163.com.
  • 2 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: qxm871001@sxtcm.edu.cn.
  • 3 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: 3223106166@qq.com.
  • 4 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: w199909202022@163.com.
  • 5 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: zhangyl@sxtcm.edu.cn.
  • 6 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: L-haixin@hotmail.com.
  • 7 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: Jhren@sxtcm.edu.cn.
  • 8 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: liu07071209@163.com.
  • 9 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: 1834347142@qq.com.
  • 10 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: sxzywqy001@163.com.
  • 11 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China. Electronic address: qiaoyb@sxtcm.edu.cn.
  • 12 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, 030619, China; School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, China; Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. Electronic address: sxlqs0501@sxtcm.edu.cn.
PMID: 39855316 DOI: 10.1016/j.freeradbiomed.2025.01.037
Abstract

Cardiac metabolism relies on glycogen conversion by glycolysis. Glycolysis intersects fatty acid oxidation and often directs a signal crosstalk between redox metabolites. Myocardium with ischemia/reperfusion significantly diverts from normal metabolism. Prospectively, peroxisome lies central to metabolism and redox changes, but mechanisms underlying in ischemia/reperfusion remain undefined. This work aims at investigating the potential effects and mechanisms of Salvianolic acid B (Sal B) in cardioprotection through metabolic remodeling. Following experiments, we found that Sal B is absorbed in blood and rat hearts and its cardiac absorption prevents ischemia/reperfusion injury. Sal B cardioprotection relates to gluconeogenesis activation and peroxisomal redox remodeling. Gluconeogenesis compensates glycogen synthesis through upregulating pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase. Gluconeogenic PC activity drives peroxisomal Pex2/Pex3 expressions and promotes the proliferation of peroxisome. Peroxisome quality control is enhanced with Pex5/Pex14/Pex13/Pex2 transcriptions. Nono, a non-POU domain-containing octamer-binding protein, promotes upregulation of gluconeogenic PC and peroxisomal gene transcripts through transcriptionally splicing their pre-RNAs at octamer duplex. Nono also controls the expression of SARM1/PARP1/sirtuin1 for catalyzing nicotinamide adenine dinucleotide (NAD+) consumption, leading to endurable redox capacities of peroxisome. Peroxisomal redox remodeling alters Reactive Oxygen Species (ROS) and NAD+ contents, following which NAD+ affects cardiac accumulation of physiologically harmful glucocorticoid. In the tests of Sal B combinational treatments, results indicate ROS upregulation whereas NAD+ downregulation with glucocorticoid, ROS scavenging and glucocorticoid elimination with NAD+ precursor, and NAD+ promotion with ROS scavenger, respectively. This metabolite signal crosstalk alternatively antagonizes/agonizes Sal B cardioprotective functions on electrocardiographic output and infarction. Taken together, we reported a cardiac metabolism regulation with Sal B, capable of preventing myocardium from ischemia/reperfusion injury. The metabolite signal crosstalk was achieved by coupling reaction cascades between gluconeogenesis and peroxisomal redox remodeling.

Keywords

Glucocorticoid; Gluconeogenesis; Metabolism; Myocardial ischemia/reperfusion; Nicotinamide adenine dinucleotide; Peroxisomal redox remodeling; Salvianolic acid B.

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