2. Academic Validation
  3. Interleukin-37 attenuates aortic valve lesions by inhibiting m6A-mediated IRAK-M degradation

Interleukin-37 attenuates aortic valve lesions by inhibiting m6A-mediated IRAK-M degradation

  • Cardiovasc Res. 2025 Feb 6:cvaf012. doi: 10.1093/cvr/cvaf012.
Gaopeng Xian 1 2 3 4,  Rong Huang 5,  Dongtu Hu 1 2 3 4,  Minhui Xu 1 2 3 4,  Yangchao Chen 6,  Hao Ren 2 7,  Dingli Xu 1 2 3 4,  Qingchun Zeng 1 2 3 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
  • 2 Key Laboratory for Organ Failure Research, Ministry of Education of the People's Republic of China, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, China.
  • 4 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
  • 5 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
  • 6 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
  • 7 Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
PMID: 39913240 DOI: 10.1093/cvr/cvaf012
Abstract

Aims: Calcific aortic valve disease (CAVD) has become an increasingly important global medical problem without effective pharmacological intervention. Accumulating evidence indicates that aortic valve calcification is driven by inflammation. Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator of inflammation, but its role in CAVD remains unclear.

Methods and results: Here, we stimulated aortic valve interstitial cells (AVICs) with low-dose lipopolysaccharide (LPS) to mimic the inflammatory response in aortic valve calcification and observed the expression pattern of IRAK-M. Furthermore, we generated IRAK-M-/- mice to explore the effect of IRAK-M deficiency on the aortic valve in vivo. Additionally, overexpression and knockdown experiments were performed to verify the role of IRAK-M in AVICs. MeRIP‒qPCR was used to detect the N6-methyladenosine (m6A) level of IRAK-M, and recombinant interleukin (IL)-37-treated AVICs were used to determine the regulatory relationship between IL-37 and IRAK-M. We found that IRAK-M expression was upregulated in the early stages of inflammation as part of a negative feedback mechanism to modulate the immune response. However, persistent inflammation increased overall m6A levels, ultimately leading to reduced IRAK-M expression. In vivo, IRAK-M-/- mice exhibited a propensity for aortic valve thickening and calcification. Overexpression and knockdown experiments showed that IRAK-M inhibited inflammation and osteogenic responses in AVICs. In addition, IL-37 restored IRAK-M expression by inhibiting m6A-mediated IRAK-M degradation to suppress inflammation and aortic valve calcification.

Conclusions: Our findings confirm that inflammation and epigenetic modifications synergistically regulate IRAK-M expression. Moreover, IRAK-M represents a potential target for mitigating aortic valve calcification. Meanwhile, IL-37 exhibited inhibitory effects on CAVD development both in vivo and in vitro, giving us hope that CAVD can be treated with drugs rather than surgery.

Keywords

Calcific aortic valve disease; Inflammation; Interleukin-1 receptor associated kinase M; Interleukin-37; N6-methyladenosine.

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