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Marine-Derived Piericidin Diglycoside S18 Alleviates Inflammatory Responses in the Aortic Valve via Interaction with
Shunyi Li1, Jianglian She2,3, Jingxin Zeng1,4
1State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Insights
Piericidin diglycoside S18 combats calcific aortic valve disease (CAVD) by reducing inflammation and mitochondrial stress in human aortic valve interstitial cells (HAVICs). This compound shows therapeutic potential for CAVD by directly interacting with interleukin-37.
Area of Science:
- Biochemistry and Molecular Biology
- Cardiovascular Research
- Pharmacology
Background:
- Calcific aortic valve disease (CAVD) is a common condition in the elderly, leading to valve dysfunction.
- Osteoblastic differentiation of human aortic valve interstitial cells (HAVICs) driven by inflammation is key to CAVD.
- Current treatments for CAVD are limited, highlighting the need for novel therapeutic agents.
Purpose of the Study:
- To investigate the anti-inflammatory effects of piericidin glycosides on human aortic valve interstitial cells (HAVICs).
- To elucidate the mechanism of action of S18, a specific piericidin diglycoside, in mitigating inflammation and mitochondrial stress.
- To evaluate the therapeutic potential of S18 in a mouse model of calcific aortic valve disease (CAVD).
Main Methods:
- Lipopolysaccharide (LPS) was used to induce inflammatory responses in HAVICs.
- The effect of S18 on LPS-induced inflammation, mitochondrial stress, and interleukin-37 (IL-37) expression was assessed.
- IL-37 knockdown using siRNA was performed to confirm its role in S18's anti-inflammatory action.
- Aortic valve lesions were analyzed in IL-37 transgenic mice treated with S18.
- Microscale thermophoresis (MST) and docking analysis were used to study the binding activity of piericidin analogues with IL-37.
Main Results:
- S18 significantly suppressed LPS-induced inflammatory responses and mitochondrial stress in HAVICs in an IL-37-dependent manner.
- Knockdown of IL-37 exacerbated inflammation and mitochondrial stress, while also blocking the anti-inflammatory effects of S18.
- S18 treatment alleviated aortic valve lesions in a mouse model of CAVD.
- Piericidin diglycosides, unlike monoglycosides, demonstrated significant IL-37 binding activity.
Conclusions:
- Piericidin diglycoside S18 directly binds to IL-37, suppressing inflammatory responses in HAVICs and reducing aortic valve lesions in mice.
- S18 represents a promising therapeutic candidate for preventing the progression of calcific aortic valve disease (CAVD).
- Targeting the IL-37 pathway with S18 offers a novel strategy for managing CAVD.
Abstract:
Calcific aortic valve disease (CAVD) is a valvular disease frequently in the elderly individuals that can lead to the valve dysfunction. Osteoblastic differentiation of human aortic valve interstitial cells (HAVICs) induced by inflammation play a crucial role in CAVD pathophysiological processes. To date, no effective drugs for CAVD have been established, and new agents are urgently needed. Piericidin glycosides, obtained from a marine-derived Streptomyces strain, were revealed to have regulatory effects on mitochondria in previous studies. Here, we discovered that 13-hydroxypiericidin A 10-O-α-D-glucose (1→6)-β-D-glucoside (S18), a specific piericidin diglycoside, suppresses lipopolysaccharide- (LPS) induced inflammatory responses of HAVICs by alleviating mitochondrial stress in an interleukin (IL)-37-dependent manner. Knockdown of IL-37 by siRNA not only exaggerated LPS-induced HAVIC inflammation and mitochondrial stress but also abrogated the anti-inflammatory effect of S18 on HAVICs. Moreover, S18 alleviated aortic valve lesions in IL-37 transgenic mice of CAVD model. Microscale thermophoresis (MST) and docking analysis of five piericidin analogues suggested that diglycosides, but not monoglycosides, exert obvious IL-37-binding activity. These results indicate that S18 directly binds to IL-37 to alleviate inflammatory responses in HAVICs and aortic valve lesions in mice. Piericidin diglycoside S18 is a potential therapeutic agent to prevent the development of CAVD.
