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Published on: July 13, 2018
Subthreshold Thermal Stress Aggravates Methamphetamine-Induced Cardiomyocyte Pyroptosis via the Mitochondrial
Mengmeng Wang1, Congcong Hou2, Menglian Hu2
1Clinical Medical College, Hebei University, Baoding 071000, China.
Abstract:
Methamphetamine (METH)-induced cardiomyocyte injury is the leading cause of mortality beyond acute intoxication. METH abuse often occurs in crowded, poorly ventilated environments, and even moderately high ambient temperatures exacerbate METH-related cardiovascular emergencies. However, the underlying mechanisms by which environmental factors drive the progression of cardiac diseases remain poorly understood. This study modeled the real-world scenario in vivo by exposing mice to METH under normothermic condition (NC, 22 °C) or subthreshold thermal stress (STS, 28 °C, a mild thermal challenge for mice) conditions, and in vitro by using H9c2 cardiomyocytes exposed to METH at 37 °C or 39 °C. STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial ultrastructural damage, and oxidative stress (p < 0.05). Mechanistically, the co-exposure impaired mitochondrial respiratory chain complex I and led to excessive mitochondrial ROS (mtROS) production, activating the pro-apoptotic protein BAX, causing mitochondrial outer membrane (MOM) permeabilization and the cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA-mediated NLRP3 inflammasome activation subsequently executed cardiomyocyte pyroptosis via caspase-1/Gasdermin D (p < 0.05). Crucially, the mitochondria-targeted antioxidant mitoquinone (MitoQ) substantially attenuated the aggravated cardiotoxicity by scavenging the initial mtROS (p < 0.05), thereby preventing the activation of the downstream BAX/mtDNA/NLRP3 axis. These findings provide evidence for a defined signaling basis for this drug-environment interaction and highlight mitochondrial redox modulation as a potential therapeutic strategy for psychostimulant-associated cardiovascular injury.
Insights
Environmental heat stress worsens methamphetamine (METH) cardiotoxicity by damaging mitochondria and triggering cell death pathways. Targeting mitochondrial reactive oxygen species (ROS) with antioxidants like MitoQ may protect against METH-induced heart injury.
Area of Science:
- Cardiovascular Toxicology
- Environmental Health
- Mitochondrial Biology
Background:
- Methamphetamine (METH) abuse is a significant cause of cardiac injury and mortality.
- Environmental factors, such as elevated ambient temperatures, can exacerbate METH-related cardiovascular risks.
- The precise mechanisms linking environmental stressors to METH cardiotoxicity are not fully understood.
Purpose of the Study:
- To investigate how subthreshold thermal stress (STS) influences METH-induced cardiomyocyte injury.
- To elucidate the molecular pathways involved in the combined effects of METH and heat on cardiac cells.
- To evaluate the therapeutic potential of targeting mitochondrial oxidative stress.
Main Methods:
- In vivo studies exposed mice to METH under normothermic (22 °C) or STS (28 °C) conditions.
- In vitro studies used H9c2 cardiomyocytes exposed to METH at 37 °C or 39 °C.
- Assessed cardiac dysfunction, mitochondrial damage, oxidative stress, and key signaling molecules (BAX, mtDNA, NLRP3 inflammasome, caspase-1/Gasdermin D).
Main Results:
- STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial damage, and oxidative stress.
- Co-exposure impaired mitochondrial respiratory chain complex I, increased mitochondrial ROS (mtROS), and activated the BAX/mtDNA/NLRP3 inflammasome axis, leading to pyroptosis.
- Mitoquinone (MitoQ) treatment attenuated METH cardiotoxicity by scavenging mtROS and inhibiting downstream apoptotic and pyroptotic pathways.
Conclusions:
- Subthreshold thermal stress exacerbates METH-induced cardiotoxicity through mitochondrial dysfunction and oxidative stress.
- The BAX/mtDNA/NLRP3 inflammasome pathway is critical in mediating METH and heat-induced cardiomyocyte pyroptosis.
- Mitochondrial redox modulation, specifically targeting mtROS, represents a promising therapeutic strategy for psychostimulant-associated cardiovascular injury.
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