Fibroblasts-specific p16INK4a exacerbates inflammageing-mediated post-infarction ventricular remodelling through interacting with STAT3 to regulate NLRP3 transcription

Background and Aims

Inflammageing represents both a critical pathophysiological hallmark and independent risk factor for myocardial infarction (MI), with age-related increases observed in MI incidence and severity of post-MI ventricular remodelling. Novel therapeutic strategies targeting inflammageing-driven mechanisms are urgently required to attenuate adverse ventricular remodelling following MI. This investigation was designed to elucidate the impact of fibroblast-specific p16^INK4a on inflammageing-associated ventricular remodelling after MI and to develop a targeted nanotherapy to mitigate this process.

Methods and Results

We found that p16-mediated inflammageing positively correlated with the severity of post-infarction ventricular remodelling in patients. POSTN-driven p16^INK4a knockout improved cardiac function, and reduced ventricular remodelling, myocardial inflammation and NLRP3 signalling activation following MI through downregulating STAT3-mediated NLRP3 inflammasome and upregulating glutathione metabolism pathway in fibroblasts. P16^INK4a overexpression induced NLRP3 signalling activation through upregulating NLRP3 transcribed by STAT3 in fibroblasts. In terms of mechanisms, p16^INK4a interacted with STAT3, which depended on the SH2 domain of STAT3; P16^INK4a promoted the interaction of EZH2 and STAT3, increased the di-methylation on K49 and phosphorylation on Y705 of STAT3 by EZH2, and promoted NLRP3 transcription through regulating histone modification in the NLRP3 promoter by interfering the formation of Bmi-1-EZH2 or Bmi-1-BCL6 complex in fibroblasts. Injection of p16^INK4a-accumulated ageing cardiac fibroblasts, or p16^INK4a overexpression adenovirus aggravated profibrosis and proinflammation in MI area. However, a novel FH peptide ‘FHKHKSPALSPV’-neutrophil membrane proteins (NMPs)-artificial lipid (Li) membranes-mesoporous silica nanoparticle (MSN) core (FNLM)-nanocaged p16^INK4a-siRNA, as a newly constructed nanomaterial drug, could prevent post-infarction ventricular remodelling through inhibiting NLRP3 transcription in targeted cardiac fibroblasts and ameliorating proinflammation and profibrosis.

Conclusions

P16^INK4a drives inflammageing-mediated post-MI ventricular remodeling by activating STAT3/NLRP3 signaling in fibroblasts. Targeting p16^INK4a via FNLM-siRNA nanotherapy represents a novel strategy to ameliorate adverse cardiac remodelling, offering translational potential for clinical intervention.

Key points

• Mechanistic Insight: P16^INK4a activates NLRP3 transcription via STAT3-EZH2 crosstalk, disrupting epigenetic complexes (Bmi-1-EZH2/BCL6) to exacerbate post-MI remodelling.
• Therapeutic Innovation: A fibroblast-targeted FNLM nanoparticle delivering p16^INK4a-siRNA effectively silences NLRP3, reducing post-MI inflammageing.
• Translational Impact: This study identifies p16^INK4a-STAT3 as a druggable axis and proposes FNLM-p16^INK4a-siRNA as a promising nanotherapy for clinical post-MI care.