Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

Chowdhury S Abdullah,James Traylor,Mohammad Alfrad Nobel Bhuiyan,A Wayne Orr,Richa Aishwarya,Sunitha Chandran,Mahboob Morshed,Naznin Sultana Remex,Gopi K Kolluru,Shafiul Alam,Brandon Hartman,Connie L Arnold,Sumitra Miriyala,Nicholas E Goeders,Xiuping Yu,Karen Y Stokes ,Christopher G Kevil,Manikandan Panchatcharam,Judy A King ,Sadia Nitu,Matthew D Woolard,Paari Dominic,Md Shenuarin Bhuiyan

doi:10.1038/s42003-020-01408-z

Abstract

Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.

Highlights

1234567890():,; Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use
We examined the tissue from 34 humans left ventricular (LV) heart sections from autopsy who were determined to be METH positive as the result of toxicological studies
We found that the hearts of human METH users exhibit fibrotic remodeling, irrespective of the cause of death, underscoring the underappreciated cardiotoxic pathologies associated with METH abuse in humans

Summary

Introduction

1234567890():,; Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. We show that Sigmar[1] is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar[1] expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. METH abuse associated with cardiovascular toxicity includes hypertension, tachycardia, cardiac arrhythmia, acute coronary vasospasm, myocardial infarction, and cardiomyopathy[1,2,6,7,8]. Reports of the histopathological characteristics present in the hearts of METH users are scarce and most of the studies used only a very small number of samples[9,12,13]

Methods

Results

Conclusion