Omics · study · 2026
Mild cold exposure mitigates ischemic heart injury through indole-3-acetamide–AHR-mediated SMAD2 proteolysis
Listed in NCBI GEO
Ambient temperature profoundly influences organismal metabolism, physiology, and disease.
Description
While cold exposure is a well-recognized risk factor for the onset of myocardial infarction (MI), its impact on the injured heart after MI remains unexplored. Here, we demonstrate that a mild cold exposure (MCE) regimen at 16oC improved mice systolic function post-MI compared to the controls kept at room temperature.
Integrative multi-omics analyses revealed a critical link between a cold-inducible tryptophan metabolite indole-3-acetamide (I3AM) and cardiac fibrosis in post-MI hearts. MCE elevated I3AM levels in serum and heart tissue and upregulated gut indole-related metabolic pathways; which was necessary to attenuate cardiac fibrotic remodeling by inhibiting SMAD2/3 signaling and fibroblast activation. Mechanistically, I3AM acts as a ligand for the aryl hydrocarbon receptor (AHR).
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I3AM-bound AHR promoted ubiquitination and proteasomal degradation of SMAD2. Treatment with I3AM recapitulated the cardioprotective effects of MCE, while genetic or pharmacological inhibition of AHR abolished the benefits of both MCE and I3AM in MI mice. In patients with and without heart failure, serum I3AM levels correlated positively with cardiac function, underscoring its clinical relevance.
Our findings unveil a previously unrecognized metabolic-proteolytic axis triggered by MCE and identify the temperature responsive I3AM-AHR-SMAD pathway as a potential therapeutic target for ischemic hearts.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322807 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322807 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1428991 ncbi.nlm.nih.gov/bioproject/PRJNA1428991 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Disease 75% · Heart 75% · Myocardial infarction 75%
Related
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE322807 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[anatomy].local:anatomy:heart | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:myocardial-infarction | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |