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  • Title: Antiretroviral drug-induced endothelial dysfunction is improved by dual PPARα/γ stimulation in obesity.
    Author: Kamau F, Strijdom H, Mwangi P, Blackhurst D, Imperial E, Salie R.
    Journal: Vascul Pharmacol; 2019 Oct; 121():106577. PubMed ID: 31284000.
    Abstract:
    Obesity rates are rising in HIV-infected populations; however, the putative role of highly active antiretroviral therapy (HAART) in the development of endothelial and cardiovascular derangements in the presence of pre-existing overweight/obesity is unclear. Although dual peroxisome proliferator-activated receptors-alpha/gamma (PPARα/γ) stimulation mitigates HAART-induced metabolic dysfunction, vascular effects are unresolved. To investigate whether HAART induces vascular dysfunction in obesity and to explore the underlying mechanisms of PPARα/γ stimulation, male Wistar rats were placed on a high-calorie diet for 16 weeks. After 10 weeks, HAART (lopinavir/ritonavir, azidothymidine/lamivudine) with/without PPARα/γ agonist, Saroglitazar, was administered daily for six weeks. Excised thoracic aorta rings were subjected to isometric tension studies and Western blot measurements. HAART+Saroglitazar-treated obese animals recorded lower adiposity indices (4.3 ± 0.5%) vs. HAART only-treated obese rats (5.6 ± 0.3%; p < .01). Maximum acetylcholine-induced vasorelaxation (Rmax), was lower in obese+HAART group (76.10 ± 3.58%) vs. obese control (101.40 ± 4.75%; p < .01). However, Rmax was improved in obese+ HAART+Saroglitazar (101.00 ± 3.12%) vs. obese+HAART rats (p < .001). The mean LogEC50 was improved in obese+HAART+Saroglitazar vs. obese+HAART group; p = .003. Improved endothelial function in obese+ HAART+Saroglitazar group was associated with upregulation of eNOS, PKB/Akt and downregulated p22-phox expression vs. obese+HAART group. Therefore, PPARα/γ stimulation attenuated HAART-induced endothelial dysfunction by upregulating vasoprotective eNOS, PKB/Akt signaling and downregulating pro-oxidative p22-phox expression.
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