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HSC70-JNK-BAG3 complex is critical for cardiomyocyte protection of BAG3 through its PXXP and BAG structural domains

Ling-Ling Zhao1, Jiao-Na Gu1, Xiao-Fang Zhu1

  • 1Cardiovascular Laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, 226001 Nantong, China.

Frontiers in Bioscience (Landmark Edition)
|June 23, 2021
PubMed

Insights

Bcl-2 associated athanogene 3 (BAG3) protects cardiomyocytes from hypoxia/reoxygenation injury. Its PXXP and BAG domains are crucial for this protective effect, interacting with HSC70 and JNK signaling.

Area of Science:

  • Cardiovascular Biology
  • Cellular Stress Response
  • Molecular Cardiology

Background:

  • Bcl-2 associated athanogene 3 (BAG3) is known to have anti-apoptotic effects in the heart.
  • The specific structural domains of BAG3 responsible for its cardioprotective functions, particularly under stress, require further elucidation.

Purpose of the Study:

  • To investigate the role of BAG3 and its PXXP and BAG domains in protecting cardiomyocytes against hypoxia/reoxygenation (H/R) induced apoptosis.
  • To elucidate the molecular mechanism underlying BAG3-mediated cardioprotection during H/R stress.

Main Methods:

  • Overexpression of BAG3 and its mutants in neonatal and adult rat cardiomyocytes (NRCMs and ARCMs).
  • Assessment of apoptosis using propidium iodide (PI) staining, cleaved caspase-3, and TUNEL staining.
  • Co-immunoprecipitation (Co-IP) to identify binding partners of BAG3, specifically HSC70 and JNK.

Main Results:

  • Overexpression of BAG3 significantly reduced H/R-induced injury in both NRCMs and ARCMs.
  • The PXXP and BAG domains of BAG3 were identified as essential for its protective effect against H/R stress.
  • BAG3 interacts with HSC70 and JNK, and these interactions are critical for attenuating cardiomyocyte apoptosis via the JNK signaling pathway.

Conclusions:

  • BAG3 exerts a protective effect against H/R-induced cardiomyocyte apoptosis.
  • The PXXP and BAG domains of BAG3 are critical for its cardioprotective function, mediated through interactions with HSC70 and JNK.
  • These findings suggest BAG3's PXXP and BAG domains as potential therapeutic targets for ischemic cardiomyopathy.

Keywords:
ApoptosisBAGBAG3CardiomyocytesHypoxiaPXXP domain

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