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Published on: March 29, 2024
Fluorofenidone ameliorates pressure overload-induced heart failure by stabilizing SERCA2a in male mice
Quan Liu1, Huayang Li1, Jiantao Chen1
1Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Insights
Fluorofenidone prevents heart failure (HF) progression by directly interacting with cardiac calcium pump SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a). This drug inhibits WWP1-mediated degradation, offering a potential new therapy for HF.
Area of Science:
- Cardiovascular Biology
- Molecular Pharmacology
- Drug Discovery
Background:
- Reduced cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) expression and activity are key indicators of heart failure (HF).
- Current therapies targeting SERCA2a for HF treatment remain limited.
- Fluorofenidone has demonstrated significant enhancement of cardiomyocyte function.
Purpose of the Study:
- To investigate the therapeutic potential of fluorofenidone in preventing pressure overload-induced heart failure.
- To identify the direct molecular target of fluorofenidone in the context of HF.
- To elucidate the mechanism by which fluorofenidone exerts its cardioprotective effects.
Main Methods:
- Drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) were employed to identify fluorofenidone's binding partner.
- Interaction studies focused on fluorofenidone, SERCA2a, and WW domain-containing E3 ubiquitin protein ligase 1 (WWP1).
- Experiments involved SERCA2a knockdown in mice subjected to pressure overload to assess fluorofenidone's efficacy.
Main Results:
- SERCA2a was identified as a direct binding target of fluorofenidone.
- Fluorofenidone was shown to inhibit the interaction between WWP1 and SERCA2a, reducing WWP1-mediated polyubiquitination of SERCA2a.
- Specific amino acid residues (Gln758, Asp812, Glu917) within SERCA2a are crucial for fluorofenidone binding.
- SERCA2a knockdown diminished the protective effects of fluorofenidone against pressure overload-induced HF in male mice.
Conclusions:
- Fluorofenidone demonstrates significant cardioprotective effects against pressure overload-induced HF by directly targeting and stabilizing SERCA2a.
- The mechanism involves preventing WWP1-mediated degradation of SERCA2a.
- Fluorofenidone represents a promising therapeutic candidate for HF, warranting further investigation in preclinical and clinical studies.
Abstract:
Reduced expression and activity of cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a), causing intracellular calcium dyshomeostasis, are regarded as hallmarks of heart failure (HF). However, effective SERCA2a-targeted therapies for HF treatment have not been identified. Here, we show that fluorofenidone, previously reported to enhance cell shortening, contraction and relaxation of cardiomyocytes by nearly 100%, prevents the progression of pressure overload-induced HF. Combining drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) approaches, we identify SERCA2a as a direct binding partner of fluorofenidone. Mechanistically, fluorofenidone attenuates the binding of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) to SERCA2a and inhibits WWP1-mediated K27-linked polyubiquitination of SERCA2a. Moreover, Gln758, Asp812 and Glu917 are essential for the fluorofenidone-SERCA2a interaction. SERCA2a knockdown markedly attenuated the cardioprotective effects of fluorofenidone on pressure overload-induced HF in male mice. Together, these findings highlight the therapeutic potential of fluorofenidone for HF treatment. Nevertheless, further preclinical and clinical studies are required to fully evaluate its in vivo efficacy and safety before clinical translation.
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