W Lewis

..In transgenic mice, AZT treatment worsens molecular and ultrastructural features of cardiomyopathy. HIV-1 constructs and AZT each contribute to cardiac dysfunction in this murine model of AIDS cardiomyopathy...

..Transgenic mice (TG) expressing human DNC targeted to murine myocardium served to define mitochondrial events from NRTIs in vivo and findings were corroborated by biochemical events in vitro...

..Further studies will help us unravel mechanisms of NRTI MT and the natural history of mitochondrial biogenesis in humans and other mammalian systems...

..Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs...

..The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM...

..These TG target the selected HIV-1 genes expressed in cardiac ventricular myocytes. Tissue-specific targeting of this type enables us to define structural and functional effects of specific HIV-1 gene products on the cardiac myocyte...

..With increased use of NRTIs, mtDNA mutations may become increasingly important pathophysiologically. One important future goal is to prevent or attenuate the side effects so that improved efficacy is achieved...

..Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself...

..Because it is possible that more than 1 of these factors is present in a given patient inflicted with AIDS, a multifactorial pathogenesis in AIDS cardiomyopathy must be considered...

..No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice...

..Each transgenic approach is a model system that affords a distinct opportunity to explore the pathogenesis and pathophysiology of AIDS CM...

..NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity...

..As dysfunctional changes are ameliorated by decreasing and worsened by increasing H(2)O(2) abundance, oxidative stress from H(2)O(2) is crucial pathogenetically in AZT-induced mitochondrial CM...

..Mechanisms of mitochondrial toxicity are reviewed with respect to key cell biological, pathological, and pharmacological events...

..Histopathologically, perivascular fibrosis and interstitial fibrosis were evident in cocaine-treated TG. Data suggest that additive cardiac insults (from AIDS and cocaine) result in combined deleterious effects...

..Tat caused cardiac dysfunction in this TG and may impact on cardiomyopathy in acquired immunodeficiency syndrome...

..This chapter summarizes data from TG models that help unravel the individual and combined effects of HIV-1 infection and NRTI therapy on mouse physiology. Emphasis is placed on cardiac mitochondrial toxicity of NRTIs used in HIV/AIDS...

..However, little is known about the roles of PPARgamma in the heart. The present study is to investigate in vivo role(s) of PPARgamma in the heart...

..Clinical observations and in vitro and in vivo studies support various mechanisms of CM. This perspective highlights some of the hypotheses and focuses on mitochondrial-associated pathways of NRTI- related CM...

..Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy...

..EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs...

..LCM-captured renal proximal tubules from TGs showed decreased mtDNA abundance with tenofovir. The results indicate that tenofovir targets mitochondrial toxicity on the renal proximal tubule in an AIDS model...

..These results indicate that treatment with ABC has no visible cardiotoxicity in these adult mice exposed for 5 weeks compared to findings with other antiretroviral NRTI studies and support some claims for its relative safety...

..In all cohorts, LV end-diastolic dimension remained unchanged. This novel cardiac-targeted overexpression of hTMPK helps define the role of TMPK in mitochondrial toxicity of antiretrovirals...

..It is possible that these agents are not adequately delivered to the subcellular sites of superoxide production...

..These results indicate that NRTIs impair endothelium-dependent relaxation by increasing superoxide levels and suggest that NRTI therapy contributes to cardiovascular complications in acquired immunodeficiency syndrome...

..Since some Vpr cardiomyocytic effects resemble those found in terminally differentiated immunocytes, some pathogenetic mechanisms may be shared at the subcellular level...

..We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases...

..In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death...

..This review characterizes the pharmacological mechanisms and pathways that are involved in mitochondrial dysfunction caused by NRTIs, and suggests opportunities for future pharmacological research...

..The impact of oxidative stress on cardiovascular disease is likely to increase because patients with HIV infection are living longer as a result of effective antiretroviral therapy...

..These deleterious events may be potentiated in acquired immunodeficiency syndrome (AIDS) by human immunodeficiency virus (HIV) infection itself, coinfection (e.g., viral hepatitis), aging, substance, and alcohol use...

..Abnormalities in beta-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes...

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..Myofibrillar, nuclear and mitochondrial volumes are analyzed quantitatively (by transmission electron microscopy [TEM]). Volume fractions of extracellular matrix and of myocytes are determined morphometrically (light and TEM). ..

..Biochemical, molecular and pathological changes (above) are ameliorated. This serves as a "proof of principle". ..

..AIM 2: to define CM from HAART microscopically and ultrastructurally using morphometric methods. AIM 3: to define cardiac performance in CM from HAART echocardiographically and using Langendorff preparations. ..

..HYPOTHESIS 4: mtDNA depletion (from any above) causes or results from oxidative stress. Antioxidants ameliorate oxidative stress from NRTIs by decreasing oxidation of mtDNA. ..

..Experiments offer insights into improving therapy with antiretrovirals used in AIDS. ..

..HYPOTHESIS 4: mtDNA depletion (from any above) causes or results from oxidative stress. Antioxidants ameliorate oxidative stress from NRTIs by decreasing oxidation of mtDNA. ..

..HYPOTHESIS 4: mtDNA depletion (from any above) causes or results from oxidative stress. Antioxidants ameliorate oxidative stress from NRTIs by decreasing oxidation of mtDNA. ..

..Experiments offer insights into improving therapy with antiretrovirals used in AIDS. ..

..Biosynthetic labeling of polypeptides is determined in isolated mitochondria. Altered expression of mtRNA and mitochondrial proteins reflect altered energy genesis. (End of Abstract) ..

..Immuno-LM and immuno-TEM identify cellular and subcellular alterations. ..

..Ultimately, information obtained may help to formulate testable hypotheses about pathogenesis and treatment of cardiomyopathy in HIV/AIDS and cocaine. ..