Methamphetamine-induced changes in myocardial gene transcription are sex-dependent

Abstract

Background Prior work demonstrated that female rats (but not their male littermates) exposed to methamphetamine become hypersensitive to myocardial ischemic injury. Importantly, this sex-dependent effect persists following 30 days of subsequent abstinence from the drug, suggesting that it may be mediated by long term changes in gene expression that are not rapidly reversed following discontinuation of methamphetamine use. The goal of the present study was to determine whether methamphetamine induces sex-dependent changes in myocardial gene expression and whether these changes persist following subsequent abstinence from methamphetamine. Results Methamphetamine induced changes in the myocardial transcriptome were significantly greater in female hearts than male hearts both in terms of the number of genes affected and the magnitude of the changes. The largest changes in female hearts involved genes that regulate the circadian clock (Dbp, Per3, Per2, BMal1, and Npas2) which are known to impact myocardial ischemic injury. These genes were unaffected by methamphetamine in male hearts. All changes in gene expression identified at day 11 returned to baseline by day 30. Conclusions These data demonstrate that female rats are more sensitive than males to methamphetamine-induced changes in the myocardial transcriptome and that methamphetamine does not induce changes in myocardial transcription that persist long term after exposure to the drug has been discontinued.

Maternal use of methamphetamine induces sex‐dependent changes in myocardial gene expression in adult offspring

“…These genes were not altered in hearts of adult rats following prenatal exposure to methamphetamine. Likewise, prenatal methamphetamine exposure in the present study induced changes in proteins that have been implicated in heart failure (DDAH2 and Bdh1) and function of the major histocompatibility complex (RT‐1Bb, RT1‐CE7, RT1‐CE15, RT1‐A1) but were not significantly impacted when methamphetamine was administered during adulthood (Chavva et al, 2021 ). Thus, exposure to methamphetamine during either the prenatal period or during early adulthood both results in a female specific phenotype that is characterized by myocardial hypersensitivity to ischemic injury changes in cardiac gene expression that occur predominately in female hearts.…”

“…This sex‐dependent cardiac phenotype was similar to that observed following prenatal exposure to methamphetamine (Rorabaugh et al, 2016 , 2017 ). RNA sequencing of hearts from these animals identified 340 changes in gene expression 24 h after the final methamphetamine injection (Chavva et al, 2021 ). Similar to the present study, the vast majority (283 out of 340; 83%) of these changes in cardiac gene expression occurred exclusively in female hearts.…”

“…Similar to the present study, the vast majority (283 out of 340; 83%) of these changes in cardiac gene expression occurred exclusively in female hearts. Furthermore, the magnitude of the changes was significantly greater in female hearts than male hearts when the animals were exposed to methamphetamine during early adulthood (Chavva et al, 2021 ). Thus, the female heart is more susceptible to changes in cardiac gene expression regardless of whether methamphetamine exposure occurs during the prenatal period or during early adulthood.…”

Consecutive treatments of methamphetamine promote the development of cardiac pathological symptoms in zebrafish

“…Interestingly, this process does not appear to be mediated by the neuronal system [63]. Recent research has indicated that GPCRs may also play a role in producing detrimental cardiac effects of Meth, including arrhythmia, fibrosis, cardiomyopathy, and tissue remodeling [64,65]. As depicted in Fig 3A, cAMP interfaces with numerous factors within the GPCR pathway that may induce such cardiovascular effects [66].…”

NPAS2, A Circadian Hemeprotein and Gas-Responsive Transcription Factor

“…Interestingly, NPAS2 was comprised in the set of genes found deregulated in myocardial transcriptome upon methamphetamine challenge. These genetic changes showed sexspecific pattern and the number of deregulated genes and the degree of the variation were significantly greater in female hearts respect to male hearts [108]. The role played by altered regulation of circadian genes in the pathogenesis of cardiovascular disease seems to be corroborated also in the case of cerebrovascular events.…”