Journal Article Ppublish
PubMed: 40462499 DOI: 10.1002/ctm2.70344
Fibroblasts-specific p16 INK4a exacerbates inflammageing-mediated post-infarction ventricular remodelling through interacting with STAT3 to regulate NLRP3 transcription.
Clin Transl Med 15(6):e70344
Authors: Xin Gu, Yingqiang Du, Jin'ge Zhang, Jiyu Li, Haiyun Chen, Yujie Lin, Yue Wang, Chunli Zhang, Shiyu Lin, Nannan Hao, Chengyi Peng, Jiacheng Ge, Jin Liu, Yan Liang, Yongjie Zhang, Xiaoyan Wang, Fang Wang, Jianliang Jin
Affiliations
- Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging & Disease, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China. Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China. Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
- Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging & Disease, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China.
- The Research Center for Aging, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China.
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.
Abstract
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.
MeSH
Nanoparticles, Pharmaceutical Preparations, Cyclin-Dependent Kinase Inhibitor P16, Clinical Medicine, Fibroblasts, Membranes