An NRIP1-Centric Monocyte Immunogenetic Bridge Between Heart Failure and Ischemic Stroke

Area of Science:

• Immunology
• Cardiology
• Neurology

Background:

• Heart failure (HF) and ischemic stroke (IS) frequently co-occur, exacerbating each other.
• Circulating immune cells are implicated as a potential inflammatory bridge between these conditions.
• Key immune mediators and therapeutic targets remain largely undefined.

Purpose of the Study:

• To identify the specific immune cell lineage linking HF and IS.
• To pinpoint candidate genes and druggable targets involved in HF-IS comorbidity.
• To explore potential therapeutic interventions.

Main Methods:

• Bidirectional Mendelian randomization (MR) using genome-wide association study data.
• Single-cell transcriptomic analysis of HF and IS mouse models.
• Integration of genetic data, spatial transcriptomics, and in vitro validation.
• In silico drug prediction and molecular dynamics simulations.

Main Results:

• MR confirmed a bidirectional causal link between HF and IS.
• Expansion of inflammatory Ly6C+ monocytes was observed in both HF and IS models.
• NRIP1 was identified as a key gene, with its expression in monocytes mediating the HF-IS link.
• Retinoic acid-related small molecules, including tretinoin, showed potential for NRIP1-targeted therapy.

Conclusions:

• An NRIP1-centered monocyte network acts as a potential immune bridge in HF-IS comorbidity.
• Tretinoin represents a promising therapeutic entry point for NRIP1-targeted intervention.
• This study elucidates a novel mechanism and therapeutic strategy for co-occurring HF and IS.