Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Novel Role of Hyaluronic Acid and Proteoglycan Link Protein 1 (HAPLN1) in Delaying Vascular Endothelial Cell Senescence

  • Dan Zhou (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Ji Min Jang (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Goowon Yang (HaplnScience Research Institute, HaplnScience Inc.) ;
  • Hae Chan Ha (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Zhicheng Fu (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Dae Kyong Kim (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University)
  • Received : 2023.05.13
  • Accepted : 2023.06.23
  • Published : 2023.11.01
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Abstract

Cardiovascular diseases (CVDs) are the most common cardiovascular system disorders. Cellular senescence is a key mechanism associated with dysfunction of aged vascular endothelium. Hyaluronic acid and proteoglycan link protein 1 (HAPLN1) has been known to non-covalently link hyaluronic acid (HA) and proteoglycans (PGs), and forms and stabilizes HAPLN1-containing aggregates as a major component of extracellular matrix. Our previous study showed that serum levels of HAPLN1 decrease with aging. Here, we found that the HAPLN1 gene expression was reduced in senescent human umbilical vein endothelial cells (HUVECs). Moreover, a recombinant human HAPLN1 (rhHAPLN1) decreased the activity of senescence-associated β-gal and inhibited the production of senescence-associated secretory phenotypes, including IL-1β, CCL2, and IL-6. rhHAPLN1 also downregulated IL-17A levels, which is known to play a key role in vascular endothelial senescence. In addition, rhHAPLN1 protected senescent HUVECs from oxidative stress by reducing cellular reactive oxygen species levels, thus promoting the function and survival of HUVECs and leading to cellular proliferation, migration, and angiogenesis. We also found that rhHAPLN1 not only increases the sirtuin 1 (SIRT1) levels, but also reduces the cellular senescence markers levels, such as p53, p21, and p16. Taken together, our data indicate that rhHAPLN1 delays or inhibits the endothelial senescence induced by various aging factors, such as replicative, IL-17A, and oxidative stress-induced senescence, thus suggesting that rhHAPLN1 may be a promising therapeutic for CVD and atherosclerosis.

Keywords

Acknowledgement

This research was supported by a Chung-Ang University Young Scientist Scholarship in 2017, and a grant from the National Research Foundation of Korea (NRF-2017M3A9D8048414) funded by the Korean government (Ministry of Science and ICT).

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