2. Academic Validation
  3. SIRT6 Protects Against Myocardial Ischemia-Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation

SIRT6 Protects Against Myocardial Ischemia-Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation

  • J Cardiovasc Transl Res. 2022 Mar 2. doi: 10.1007/s12265-021-10184-y.
Xiaokang Li 1,  Lin Liu 2,  Wenhua Jiang 3,  Manling Liu 4,  Yishi Wang 4,  Heng Ma  # 5,  Nan Mu  # 6,  Haiyan Wang  # 7
Affiliations

Affiliations

  • 1 Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, No. 1 Xinsi Rd, Xi'an, China.
  • 2 Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, No. 1 Xinsi Rd, Xi'an, 710032, China.
  • 3 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
  • 4 Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, China.
  • 5 Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, China. hengma@fmmu.edu.cn.
  • 6 Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, China. muunan@fmmu.edu.cn.
  • 7 Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, No. 1 Xinsi Rd, Xi'an, China. wanghaiyan0329@vip.163.com.
  • # Contributed equally.
PMID: 35235147 DOI: 10.1007/s12265-021-10184-y
Abstract

Impaired autophagic flux induces aging-related ischemia vulnerability, which is the hallmark pathology in cardiac aging. Our previous work has confirmed that the accumulation of charged multivesicular body protein 2B (CHMP2B), a subunit of the ESCRT-III complex, in the heart can impair Autophagy flux. However, whether CHMP2B accumulation contributes to aging-related intolerance to ischemia/reperfusion (I/R) injury and the regulatory mechanism for CHMP2B in aged heart remain elusive. The cardiac CHMP2B level was significantly higher in aged human myocardium than that in young myocardium. Increased CHMP2B were shown to inhibit autophagic flux leading to the deterioration of MI/R injury in aged mice hearts. Interestingly, a negative correlation was observed between SIRT6 and CHMP2B expression in human heart samples. Specific activation of SIRT6 suppressed CHMP2B accumulation and ameliorated Autophagy flux in aged hearts. Using myocardial-specific SIRT6 heterozygous knockout mice and recovery experiments confirmed that SIRT6 regulated myocardial CHMP2B levels. Finally, activation of SIRT6 decreased acetylation of FoxO1 to promote its transcriptional function on Atrogin-1, a muscle-specific ubiquitin Ligase, which subsequently enhanced the degradation of CHMP2B by Atrogin-1. This is a novel mechanism for SIRT6 against aging-related myocardial ischemia vulnerability, particularly by preventing excessive accumulation of Autophagy key factors.

Keywords

Aging; Atrogin-1; Autophagic flux; CHMP2B; Myocardial ischemia–reperfusion; SIRT6.

Figures
Products