2. Academic Validation
  3. Modulating Lysine Crotonylation in Cardiomyocytes Improves Myocardial Outcomes

Modulating Lysine Crotonylation in Cardiomyocytes Improves Myocardial Outcomes

  • Circ Res. 2022 Aug 19;131(5):456-472. doi: 10.1161/CIRCRESAHA.122.321054.
Wenqian Cai # 1,  Dacai Xu # 1 2,  Chui Zeng # 1,  Fan Liao 3,  Ruiqi Li 1,  Yingjiong Lin 1,  Yue Zhao 1,  Wenyan Dong 1,  Qingwen Wang 1,  Haili Yang 4,  Daqiang Wen 1,  Jianbiao Gu 1,  Weihui Shentu 5,  Hongkui Yu 5,  Xiaochun Zhang 6,  Jianrui Wei 1,  Jinzhu Duan 1 3
Affiliations

Affiliations

  • 1 Heart Center and Institute of Pediatrics (W.C., D.X., C.Z., R.L., Y.L., Y.Z., W.D., Q.W., D.W., J.G., J.W., J.D.), Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China.
  • 2 Institute Pasteur of Shanghai, Chinese Academy of Science, Shanghai (D.X.).
  • 3 School of Medicine' South China University of Technology, Guangzhou (F.L., J.D.).
  • 4 Pathology Department, The Third Affiliated Hospital of Guangzhou Medical University, China (H.Y.).
  • 5 Department of Ultrasonography (W.S., H.Y.), Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China.
  • 6 Radiology Department (X.Z.), Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China.
  • # Contributed equally.
PMID: 35920168 DOI: 10.1161/CIRCRESAHA.122.321054
Abstract

Background: Ischemic heart disease is a major global public health challenge, and its functional outcomes remain poor. Lysine crotonylation (Kcr) was recently identified as a post-translational histone modification that robustly indicates active promoters. However, the role of Kcr in myocardial injury is unknown. In this study, we aimed to clarify the pathophysiological significance of Kcr in cardiac injury and explore the underlying mechanism.

Methods: We investigated the dynamic change of both the Kcr sites and protein level in left ventricular tissues at 2 time points following sham or cardiac ischemia-reperfusion injury, followed by liquid chromatography-coupled tandem mass tag mass spectrometry. After validation of the enriched protein Kcr by immunoprecipitation and Western blot, the function and mechanism of specific Kcr sites were further investigated in vitro and in vivo by gain- or loss-of-function mutations targeting Kcr sites of selected proteins.

Results: We found that cardiac ischemia-reperfusion injury triggers preferential Kcr of proteins required for cardiomyocyte contractility, including mitochondrial and Cytoskeleton proteins, which occurs largely independently of protein-level changes in the same proteins. Those exhibiting Kcr changes were associated not only with disruption of cardiomyocyte mitochondrial, sarcomere architecture, and gap junction but also with cardiomyocyte Autophagy and Apoptosis. Modulating site-specific Kcr of selected mitochondrial protein IDH3a (isocitrate dehydrogenase 3 [NAD+] alpha) at K199 and cytoskeletal protein TPM1 (tropomyosin alpha-1 chain) at K28/29 or enhancing general Kcr via sodium crotonate provision not only protects cardiomyocyte from Apoptosis by inhibiting BNIP3 (Bcl-2 adenovirus E18 19-kDa-interacting protein 3)-mediated Mitophagy or Cytoskeleton structure rearrangement but also preserves postinjury myocardial function by inhibiting fibrosis and Apoptosis.

Conclusions: Our results indicate that Kcr modulation is a key response of cardiomyocytes to ischemia-reperfusion injury and may represent a novel therapeutic target in the context of ischemic heart disease.

Keywords

autophagy; cytoskeleton; ischemia; lysine; mitochondria; myocytes, cardiac.

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