RESUMO
Introduction: The illicit use of methamphetamine (MA), a dangerous psychostimulant has become a global epidemic. Studies have demonstrated a link between illicit substance use and cardiovascular consequences. The objective of this study was to assess whether MA use is associated with an early onset of cardiovascular diseases (CVD). Methods: Retrospective analysis was conducted using data collected from 1376 individuals at Louisiana State University Health Sciences Center - Shreveport between 2011 and 2020. Cardiovascular patients with and without a history of MA use were divided into the MA and Control groups. The age of CVD onset was assessed. Descriptive statistics for patient characteristics, Two Samples T-Test for continuous and Pearson's χ^2- tests for categorical variables were calculated. Hazard ratios (HR) and time ratios (TR) were calculated. Results: The age of CVD onset in patients with prior MA use occurred on average 8 year earlier than the age of CVD onset (mean age ± SD = 44 ± 12.04) in controls (mean age ± SD = 52 ± 10.70) (unpaired t-test, p < 0.0001). The findings were noted in both the races (Time Ratio = 0.93, 95% CI = 0.89 to 0.97, p-value < 0.001), with a striking difference in the latency to CVD onset between Black and White subjects. A 12-fold increase in subjects who showed a premature onset of CVD (<30 years of age) in the MA group was observed. Our data analysis revealed that hypertension was the most frequently observed CVD. Conclusions: MA use likely accelerates early onset of CVD and contributes to CVD complications in young adults.
RESUMO
Sigmar1 is a widely expressed molecular chaperone protein in mammalian cell systems. Accumulating research demonstrated the cardioprotective roles of pharmacologic Sigmar1 activation by ligands in preclinical rodent models of cardiac injury. Extensive biochemical and immuno-electron microscopic research demonstrated Sigmar1's sub-cellular localization largely depends on cell and organ types. Despite comprehensive studies, Sigmar1's direct molecular role in cardiomyocytes remains elusive. In the present study, we determined Sigmar1's subcellular localization, transmembrane topology, and function using complementary microscopy, biochemical, and functional assays in cardiomyocytes. Quantum dots in transmission electron microscopy showed Sigmar1 labeled quantum dots on the mitochondrial membranes, lysosomes, and sarcoplasmic reticulum-mitochondrial interface. Subcellular fractionation of heart cell lysates confirmed Sigmar1's localization in purified mitochondria fraction and lysosome fraction. Immunocytochemistry confirmed Sigmar1 colocalization with mitochondrial proteins in isolated adult mouse cardiomyocytes. Sigmar1's mitochondrial localization was further confirmed by Sigmar1 colocalization with Mito-Tracker in isolated mouse heart mitochondria. A series of biochemical experiments, including alkaline extraction and proteinase K treatment of purified heart mitochondria, demonstrated Sigmar1 as an integral mitochondrial membrane protein. Sigmar1's structural requirement for mitochondrial localization was determined by expressing FLAG-tagged Sigmar1 fragments in cells. Full-length Sigmar1 and Sigmar1's C terminal-deletion fragments were able to localize to the mitochondrial membrane, whereas N-terminal deletion fragment was unable to incorporate into the mitochondria. Finally, functional assays using extracellular flux analyzer and high-resolution respirometry showed Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes. Overall, we found that Sigmar1 localizes to mitochondrial membranes and is indispensable for maintaining mitochondrial respiratory homeostasis in cardiomyocytes.
