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Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats.

Otis JS, Ashikhmin YI, Brown LA, Guidot DM - AIDS Res Ther (2008)

Bottom Line: We provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication.Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies.If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center and Emory University School of Medicine, 1670 Clairmont Road, Decatur, GA 30033, USA. jsotis@emory.edu

ABSTRACT

Background: Human immunodeficiency virus type 1 (HIV-1) infection and the consequent acquired immunodeficiency syndrome (AIDS) has protean manifestations, including muscle wasting and cardiomyopathy, which contribute to its high morbidity. The pathogenesis of these myopathies remains partially understood, and may include nutritional deficiencies, biochemical abnormalities, inflammation, and other mechanisms due to viral infection and replication. Growing evidence has suggested that HIV-1-related proteins expressed by the host in response to viral infection, including Tat and gp120, may also be involved in the pathophysiology of AIDS, particularly in cells or tissues that are not directly infected with HIV-1. To explore the potentially independent effects of HIV-1-related proteins on heart and skeletal muscles, we used a transgenic rat model that expresses several HIV-1-related proteins (e.g., Tat, gp120, and Nef). Outcome measures included basic heart and skeletal muscle morphology, glutathione metabolism and oxidative stress, and gene expressions of atrogin-1, muscle ring finger protein-1 (MuRF-1) and Transforming Growth Factor-beta1 (TGFbeta1), three factors associated with muscle catabolism.

Results: Consistent with HIV-1 associated myopathies in humans, HIV-1 transgenic rats had increased relative heart masses, decreased relative masses of soleus, plantaris and gastrocnemius muscles, and decreased total and myosin heavy chain type-specific plantaris muscle fiber areas. In both tissues, the levels of cystine (Cyss), the oxidized form of the anti-oxidant cysteine (Cys), and Cyss:Cys ratios were significantly elevated, and cardiac tissue from HIV-1 transgenic rats had altered glutathione metabolism, all reflective of significant oxidative stress. In HIV-1 transgenic rat hearts, MuRF-1 gene expression was increased. Further, HIV-1-related protein expression also increased atrogin-1 (approximately 14- and approximately 3-fold) and TGFbeta1 (approximately 5-fold and approximately 3-fold) in heart and plantaris muscle tissues, respectively.

Conclusion: We provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication. Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies. If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.

No MeSH data available.


Related in: MedlinePlus

GSH and Cys pools in heart tissues from HIV-1 transgenic rats. High performance liquid chromatography was performed on heart tissues to detect levels of the thiol pairs GSH and GSSG, and Cys and Cyss. HIV-1-related protein expression had no effect on GSH or GSSG levels (A and B), but did increase the overall oxidative state of the GSH pool (C). In contrast, Cys levels were reduced and Cyss levels were elevated in heart tissues from HIV-1 transgenic rats compared to controls (D and E, respectively). Therefore, the Cyss:Cys ratio, a marker of the overall oxidative state of the Cys pool, was significantly increased in HIV-1 transgenic rat hearts (F). *, p ≤ 0.05 vs. control.
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Figure 2: GSH and Cys pools in heart tissues from HIV-1 transgenic rats. High performance liquid chromatography was performed on heart tissues to detect levels of the thiol pairs GSH and GSSG, and Cys and Cyss. HIV-1-related protein expression had no effect on GSH or GSSG levels (A and B), but did increase the overall oxidative state of the GSH pool (C). In contrast, Cys levels were reduced and Cyss levels were elevated in heart tissues from HIV-1 transgenic rats compared to controls (D and E, respectively). Therefore, the Cyss:Cys ratio, a marker of the overall oxidative state of the Cys pool, was significantly increased in HIV-1 transgenic rat hearts (F). *, p ≤ 0.05 vs. control.

Mentions: HIV-1 infection is associated with increased oxidative stress [5]. Therefore, we next identified the effect of HIV-1-related protein expression on the glutathione (GSH) anti-oxidant system in heart and plantaris muscles. In heart tissues, no effects of the transgene were evident on the levels of GSH or glutathione disulfide (GSSG) (Fig. 2A and 2B, respectively). However, the GSSG:GSH ratio, a marker of the oxidative state of the GSH pool, was significantly elevated in heart tissues from HIV-1 transgenic rats (Fig. 2C) suggesting increased oxidative stress to this thiol pool. Heart tissues from HIV-1 transgenic rats also had significantly lower levels of cysteine (Cys), higher levels of cystine (Cyss), and an elevated Cyss:Cys ratio (Fig. 2D–F, respectively). Interestingly, both GSH and GSSG level were increased in plantaris muscles from HIV-1transgenic rats compared to controls (Fig. 3A and 3B, respectively). However, there was no difference in the GSSG:GSH ratio between these groups suggesting that the GSH pool was largely unaffected by the products of the transgene (Fig. 3C). In contrast, plantaris muscles from HIV-1 transgenic rats had increased Cyss levels and an increased Cyss:Cys ratio suggesting significant oxidative stress to this thiol pool (Fig. 3E and 3F, respectively).


Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats.

Otis JS, Ashikhmin YI, Brown LA, Guidot DM - AIDS Res Ther (2008)

GSH and Cys pools in heart tissues from HIV-1 transgenic rats. High performance liquid chromatography was performed on heart tissues to detect levels of the thiol pairs GSH and GSSG, and Cys and Cyss. HIV-1-related protein expression had no effect on GSH or GSSG levels (A and B), but did increase the overall oxidative state of the GSH pool (C). In contrast, Cys levels were reduced and Cyss levels were elevated in heart tissues from HIV-1 transgenic rats compared to controls (D and E, respectively). Therefore, the Cyss:Cys ratio, a marker of the overall oxidative state of the Cys pool, was significantly increased in HIV-1 transgenic rat hearts (F). *, p ≤ 0.05 vs. control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2365956&req=5

Figure 2: GSH and Cys pools in heart tissues from HIV-1 transgenic rats. High performance liquid chromatography was performed on heart tissues to detect levels of the thiol pairs GSH and GSSG, and Cys and Cyss. HIV-1-related protein expression had no effect on GSH or GSSG levels (A and B), but did increase the overall oxidative state of the GSH pool (C). In contrast, Cys levels were reduced and Cyss levels were elevated in heart tissues from HIV-1 transgenic rats compared to controls (D and E, respectively). Therefore, the Cyss:Cys ratio, a marker of the overall oxidative state of the Cys pool, was significantly increased in HIV-1 transgenic rat hearts (F). *, p ≤ 0.05 vs. control.
Mentions: HIV-1 infection is associated with increased oxidative stress [5]. Therefore, we next identified the effect of HIV-1-related protein expression on the glutathione (GSH) anti-oxidant system in heart and plantaris muscles. In heart tissues, no effects of the transgene were evident on the levels of GSH or glutathione disulfide (GSSG) (Fig. 2A and 2B, respectively). However, the GSSG:GSH ratio, a marker of the oxidative state of the GSH pool, was significantly elevated in heart tissues from HIV-1 transgenic rats (Fig. 2C) suggesting increased oxidative stress to this thiol pool. Heart tissues from HIV-1 transgenic rats also had significantly lower levels of cysteine (Cys), higher levels of cystine (Cyss), and an elevated Cyss:Cys ratio (Fig. 2D–F, respectively). Interestingly, both GSH and GSSG level were increased in plantaris muscles from HIV-1transgenic rats compared to controls (Fig. 3A and 3B, respectively). However, there was no difference in the GSSG:GSH ratio between these groups suggesting that the GSH pool was largely unaffected by the products of the transgene (Fig. 3C). In contrast, plantaris muscles from HIV-1 transgenic rats had increased Cyss levels and an increased Cyss:Cys ratio suggesting significant oxidative stress to this thiol pool (Fig. 3E and 3F, respectively).

Bottom Line: We provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication.Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies.If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center and Emory University School of Medicine, 1670 Clairmont Road, Decatur, GA 30033, USA. jsotis@emory.edu

ABSTRACT

Background: Human immunodeficiency virus type 1 (HIV-1) infection and the consequent acquired immunodeficiency syndrome (AIDS) has protean manifestations, including muscle wasting and cardiomyopathy, which contribute to its high morbidity. The pathogenesis of these myopathies remains partially understood, and may include nutritional deficiencies, biochemical abnormalities, inflammation, and other mechanisms due to viral infection and replication. Growing evidence has suggested that HIV-1-related proteins expressed by the host in response to viral infection, including Tat and gp120, may also be involved in the pathophysiology of AIDS, particularly in cells or tissues that are not directly infected with HIV-1. To explore the potentially independent effects of HIV-1-related proteins on heart and skeletal muscles, we used a transgenic rat model that expresses several HIV-1-related proteins (e.g., Tat, gp120, and Nef). Outcome measures included basic heart and skeletal muscle morphology, glutathione metabolism and oxidative stress, and gene expressions of atrogin-1, muscle ring finger protein-1 (MuRF-1) and Transforming Growth Factor-beta1 (TGFbeta1), three factors associated with muscle catabolism.

Results: Consistent with HIV-1 associated myopathies in humans, HIV-1 transgenic rats had increased relative heart masses, decreased relative masses of soleus, plantaris and gastrocnemius muscles, and decreased total and myosin heavy chain type-specific plantaris muscle fiber areas. In both tissues, the levels of cystine (Cyss), the oxidized form of the anti-oxidant cysteine (Cys), and Cyss:Cys ratios were significantly elevated, and cardiac tissue from HIV-1 transgenic rats had altered glutathione metabolism, all reflective of significant oxidative stress. In HIV-1 transgenic rat hearts, MuRF-1 gene expression was increased. Further, HIV-1-related protein expression also increased atrogin-1 (approximately 14- and approximately 3-fold) and TGFbeta1 (approximately 5-fold and approximately 3-fold) in heart and plantaris muscle tissues, respectively.

Conclusion: We provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication. Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies. If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.

No MeSH data available.


Related in: MedlinePlus