Methamphetamine and HIV-Tat alter murine cardiac DNA methylation and gene expression

Abstract

This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects.

The role of HIV Tat protein in HIV-related cardiovascular diseases

“…A study addressed the individual and combined effects of HIV-1 and methamphetamine on cardiac dysfunction using a transgenic mouse model of HIV infection. The results demonstrated that Tat and methamphetamine increased calcium uptake and promoted mitochondrial dysfunction in cardiomyocytes, this altered the DNA methylation and expression of CACNA1C , that encodes the alpha 1c (Cav1.2) subunit of the L-type calcium channel [ 25 ].…”

HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice

“…Tat also impaired mitochondrial quality control, reduced bioenergetic capacity, disrupted mitochondrial membrane potential, and amplified ROS formation in cultured cardiomyocytes [ 34 ]. We and others have found that Tat upregulates [Ca 2+ ] i in cultured cardiomyocytes, which is expected to increase the risk of CVDs [ 34 , 91 , 92 ]. Although the underlying mechanisms of Tat-induced mitochondrial injury are not fully understood, changes in redox status might contribute to Tat-induced mitochondrial dysfunction in cultured cardiomyocytes and astrocytes.…”

Stimulant Drugs of Abuse and Cardiac Arrhythmias

“…70 Methamphetamine can also produce epigenetic DNA methylation, thereby increasing transcription and translation of L-type calcium channels in animal models of HIV infection, a finding of potential significance in the HIV population that is known to have an increased prevalence of stimulant drug use. 71 Amphetamine-derived stimulants, including MDMA, can increase field potential duration of human inducible stem cell-derived cardiomyocytes in a concentrationdependent manner. 20 In addition, a single dose of MDMA can decrease connexin 43 expression in animal models, leading to a reduction in N-cadherin and altered calcium oscillation patterns.…”

“…70 Methamphetamine can also produce epigenetic DNA methylation, thereby increasing transcription and translation of L-type calcium channels in animal models of HIV infection, a finding of potential significance in the HIV population that is known to have an increased prevalence of stimulant drug use. 71…”