title: 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.
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States. Electronic address: ckoczor@emory.edu.
authors: Christopher A
authors: CA
authors: Koczor
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Earl
authors: E
authors: Fields
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Mark J
authors: MJ
authors: Jedrzejczak
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Zhe
authors: Z
authors: Jiao
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Tomika
authors: T
authors: Ludaway
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Rodney
authors: R
authors: Russ
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Joan
authors: J
authors: Shang
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: Rebecca A
authors: RA
authors: Torres
authors: Department of Pathology, Emory University, Atlanta, GA 30322, United States.
authors: William
authors: W
authors: Lewis
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D015658:HIV Infections / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects*; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D011401:Promoter Regions, Genetic; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine
keywords: AIDS; Epigenetics; HIV-1; Heart; Methamphetamine