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Mild cold exposure mitigates ischemic heart injury through indole-3-acetamide–AHR-mediated SMAD2 proteolysis

ABSTRACT: Ambient temperature profoundly influences organismal metabolism, physiology, and disease. 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). 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE322807 | GEO | 2026/03/09

REPOSITORIES: GEO

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Mild cold exposure mitigates ischemic heart injury through indole-3-acetamide–AHR-mediated SMAD2 proteolysis

Project description:Ambient temperature profoundly influences organismal metabolism, physiology, and disease. 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). 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.

2026-03-07 | GSE322673 | GEO

Mild cold exposure mitigates ischemic heart injury through indole-3-acetamide–AHR-mediated SMAD2 proteolysis

Project description:<p>Ambient temperature profoundly influences organismal metabolism, physiology, and disease. 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). 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.</p>

2026-03-03 | MTBLS13965 | MetaboLights

YAP Drives Assembly of a Spatially Colocalized Cellular Triad Required for Heart Renewal

Project description:After myocardial infarction (MI), the heart fails to renew, and the cardiac microenvironment is irreversibly disrupted. Inactivation of the Hippo signaling pathway can rebuild the post ischemic microenvironment and improve cardiac function. We investigated spatially resolved cellular relationships of neonatal and adult renewal-competent hearts to gain insight into inefficient mammalian heart renewal. Spatial transcriptomics (ST) and single-cell sequencing of adult control hearts and hearts expressing YAP5SA, an active version of the Hippo signaling pathway effector YAP, which models heart renewal, revealed a conserved, renewal-competent cardiomyocyte (CM) population in control hearts and amplified in YAP5SA hearts. This CM population was also found in the wildtype, renewal competent neonatal heart after myocardial infarction, as well as the adult human heart. Cardiac fibroblasts (CFs), expressing complement C3, colocalized with these CMs. In YAP5SA hearts and neonatal hearts post-MI, macrophages (MPs) expressing complement receptor C3ar1 also colocalized, creating a pro-renewal niche composed of the CM, CF and MP triad. Both C3 and C3ar1 loss-of-function in YAP5SA hearts similarly suppressed heart renewal, indicating that C3-expressing CFs, C3ar1-expressing MPs, and complement system signaling play a direct role in heart renewal

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Transcription profiling of Tbx1 function in adult myocardial infarction hearts [bulk RNA-seq]

Project description:Post-myocardial infarction (Post-MI) heart failure is an unanswered clinical challenge. Current immunological intervention trials to reduce MI damage are unsatisfactory. Tbx1, the major 22q11.2 deletion syndrome (22q11.2DS) disease gene, reactivated in cardiac lymphatic endothelial cells (LECs) to promote post-MI repair. Endothelial deletion of Tbx1 deteriorated post-MI cardiac function. To identify the initial endothelial-derived gene expression changes that are responsible for lymphangiogenesis and cell non-autonomous functions towards immune cells after MI, we enriched CD31+ endothelial cells from 5 dpMI Ctrl and Tbx1cko hearts and performed RNA-seq. In conclusion, our findings revealed that Tbx1 can promote lymphangiogenesis and alleviate excessive cardiac inflammation in post MI hearts.

2023-08-28 | GSE137063 | GEO

Comparison of gene expression in cardiac macrophages from P1 or P14 mice 3 days following MI

Project description:Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration. Total RNA was isolated from CD11b+Ly6G- cells sorted from hearts 3 days following ligation of LAD. 6 samples total: Triplicates of cells from P1 mice and from P14 mice

2014-01-31 | E-GEOD-54530 | biostudies-arrayexpress

Evaluating the effects of cardiac telomerase re-activation after myocardial infarction in adult mice

Project description:Coronary heart disease is a main cause of death in the developed world and treatment success remains modest with high mortality rates within one year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases including heart disease. Here, we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression in a mouse model of MI. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared to controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work highlights telomerase activation as a novel therapeutic strategy to prevent heart failure after MI. Mice of one year of age were left untreated (control) or injected with 5*10^11 adeno associated viruses particles of serotype 9 (AAV9) that carry either en empty expression cassette or express telomerase under control of the CMV promoter. Virus injected mice then underwent myocardial infarction induced through permenant left anterior descending artery (LAD) ligation. Mice that survived for six weeks after LAD ligation were sacrificed and 4 hearts per group (AAV9-empty or AAV9-Tert) and 3 control hearts (no virus treatment, no ligation) were subjected to total RNA isolation for micro array analysis.

2014-12-15 | E-GEOD-62973 | biostudies-arrayexpress

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Project description:While human organoid systems have provided a powerful platform in modeling diseases caused by genetic disorders, non-genetic factors, such as lifestyle and environment, are the largest attributable factors to devastating diseases like cardiovascular disease (CVD), the leading cause of death worldwide. Specifically, myocardial infarction (MI) (i.e., heart attack) makes up ~8.5% of CVD and is a common cause of heart failure with a 40% five-year mortality after the first MI. This highlights an urgent need to develop relevant human heart failure models for drug development. This is further evidenced by the disappointing performance of heart failure drugs in clinical trials during the last decade, which has been partially attributed to the distinct differences between human patient hearts and animal heart failure models. Here, we combined major non-genetic causal factors of MI with our previously established cardiac organoids to create the first human organoid model of cardiac infarction. In particular, we leveraged the diffusion limitation in 3D microtissues to recreate the nutrient diffusion gradient across infarcted hearts (i.e., infarct-border-remote zones) in human cardiac organoids to induce cardiac organotypic response to infarction. This enabled the recapitulation of major MI hallmarks in human cardiac organoids at the transcriptomic, structural and functional level.

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2024-09-21 | GSE265931 | GEO

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