Hyperthermia exacerbates methamphetamine cardiotoxicity by promoting neutrophil-dominant inflammation and Map3k6-associated p38/ERK signaling.

Authors

Congcong Hou, Xiang Li, Wenjing Zhang, Jiayin Wang, Zeying Guo, Pengli Sun, Miao Gao, Xin Ni, Zixu Wang, Di Wen, Chunling Ma

Published in

Toxicology and applied pharmacology. Pages 118083. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Methamphetamine (METH) abuse is frequently accompanied by life-threatening hyperthermia, yet the contribution of hyperthermia to METH-induced cardiac injury remains poorly defined. Here, we tested whether elevated ambient temperature amplifies METH cardiotoxicity by aggravating hyperthermia. C57BL/6 mice were exposed to different ambient temperatures (18 °C, 22 °C, or 28 °C) and treated with METH. METH rapidly increased core body temperature, whereas exposure at 28 °C further intensified hyperthermia and caused 20% mortality. In surviving mice, METH at 28 °C significantly reduced cardiac function-including heart rate, cardiac output, stroke volume, ejection fraction and fractional shortening, and induced myocardial eosinophilic degeneration, focal myofiber disruption, cardiomyocyte lysis and inflammatory cell infiltration. Cardiac transcriptomics revealed a distinct inflammatory program enriched for cytokine-cytokine receptor interaction, chemokine signaling, leukocyte chemotaxis and neutrophil migration. RT-qPCR confirmed increased cardiac expression of CCL2, CXCL1, ITGAM, ICAM-1 and MMP9, and inflammatory cytokines were also elevated. Immune-infiltration analysis identified prominent neutrophil accumulation, and gene-set enrichment analysis (GSEA) indicated activation of oxidative stress-related pathways. Among stress-related kinases, mitogen-activated protein kinase kinase kinase 6 (Map3k6, also known as ASK2) was upregulated and positively correlated with neutrophil-dominant infiltration and inflammatory markers. METH at 28 °C also increased p38 and extracellular signal-regulated kinase (ERK) phosphorylation. These findings identify elevated ambient temperature as a critical amplifier of METH-induced cardiac injury and implicate Map3k6-associated p38/ERK activation in hyperthermia-associated cardiac inflammation and functional impairment. Collectively, our results indicate that hyperthermia exacerbates METH cardiotoxicity, potentially involving Map3k6-associated p38/ERK signaling and neutrophil-dominant immune infiltration, providing new mechanistic insights into temperature-associated cardiac vulnerability following METH abuse.

PMID:
42874877
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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