2. Academic Validation
  3. p38MAPK protects against myocardial ischemia-reperfusion injury by regulating GLUT4 expression and translocation through MEF2A/MEF2C in isolated rat heart

p38MAPK protects against myocardial ischemia-reperfusion injury by regulating GLUT4 expression and translocation through MEF2A/MEF2C in isolated rat heart

  • Life Sci. 2026 May 15:393:124343. doi: 10.1016/j.lfs.2026.124343.
Weilong Gao 1,  Dan Zhang 1,  Benfa Zhang 2,  Peng Sun 3,  Ying Cao 4,  Siyuan Yang 5,  Hongjin Chen 6,  Yingnan Song 7
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Guizhou Medical University Key Laboratory of Cardiovascular Disease Basic and Clinical Research, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 561113, China.
  • 2 Guizhou Medical University Key Laboratory of Cardiovascular Disease Basic and Clinical Research, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China.
  • 3 Guizhou Medical University Key Laboratory of Cardiovascular Disease Basic and Clinical Research, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 561113, China.
  • 4 Department of Anesthesiology, The Affiliated JinYang Hospital of Guizhou Medical University, The Second People's Hospital of Guiyang, Guiyang, Guizhou, 550081, China.
  • 5 Division of Cardiac Surgery, Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, China. Electronic address: [email protected].
  • 6 Department of Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Guizhou Medical University Key Laboratory of Cardiovascular Disease Basic and Clinical Research, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Division of Cardiac Surgery, Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, China. Electronic address: [email protected].
  • 7 Department of Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Guizhou Medical University Key Laboratory of Cardiovascular Disease Basic and Clinical Research, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China; Division of Cardiac Surgery, Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, China. Electronic address: [email protected].
PMID: 41865872 DOI: 10.1016/j.lfs.2026.124343
Abstract

Aims: Myocardial ischemia-reperfusion injury (MIRI) remains a critical complication associated with cardiopulmonary bypass (CPB). This study investigated whether p38 mitogen-activated protein kinase (p38MAPK) sustains myocardial glucose uptake by controlling glucose transporter-4 (GLUT4) expression and membrane translocation through distinct myocyte enhancer factor-2 (MEF2) isoforms.

Materials and methods: MIRI was induced in Langendorff-perfused isolated rat hearts and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated neonatal rat ventricular myocytes (NRVMs) and H9C2 cells. p38MAPK was inhibited with SB203580, MEF2 isoforms were overexpressed via lentiviral transduction. and GLUT4 translocation was assessed by subcellular fractionation, Wheat Germ Agglutinin (WGA) co-staining. Akt substrate of 160 kDa (AS160) phosphorylation and Rab8a-GLUT4 interaction were also examined.

Key findings: MIRI significantly suppressed both total and phosphorylated p38MAPK, concomitant with dual-specificity Phosphatase 1 (DUSP1/MKP1) upregulation. This was associated with reduced GLUT4 expression, impaired membrane translocation, and diminished glucose uptake, while GLUT1 expression remained unchanged. SB203580 further aggravated these deficits. MEF2A and MEF2C were significantly downregulated during MIRI, whereas MEF2D was unaffected, and MEF2B was undetectable in adult cardiac tissue. Overexpression of MEF2A or MEF2C restored GLUT4 expression and promoted membrane translocation by enhancing AS160 phosphorylation at isoform-specific sites (MEF2A: Thr642/Ser588; MEF2C: Ser318/Ser341/Ser570/Ser588). This phosphorylation pattern promoted Rab8a-GLUT4 vesicle association independently of Akt activation. In contrast, MEF2D overexpression increased GLUT4 expression without facilitating membrane translocation.

Significance: These findings identify a p38MAPK-MEF2A/C-AS160-Rab8a signaling axis that drives GLUT4 expression and membrane translocation to sustain myocardial glucose uptake during MIRI. This study provides mechanistic insight into the metabolic role of p38MAPK in MIRI.

Keywords

GLUT4; Glucose metabolism; MEF2; Myocardial ischemia-reperfusion injury; P-AS160; p38MAPK.

Figures
Products