HIV viral proteins elevate blood pressure and impairs endothelial function in resistance and conduit arteries via sex specific, immune and Nox1-dependent mechanisms in mice

Taylor C. Kress, Thiago Bruder-Nascimento, Simone Kennard, Jessica L. Faulkner, Eric J. Belin de Chantemele

Research output: Contribution to journalArticlepeer-review

Abstract

Thanks to the onset of combination antiretroviral therapy (cART), patients living with HIV (PLWH) live longer but experience accelerated rates of hypertension. However, the etiology and individual contributions of repressed viral infection and cART to HIV-associated hypertension remains ill-defined. Despite cART treatment, PLWH exhibit detectable circulating levels of viral proteins leading us to hypothesize that HIV-associated hypertension is immune regulated and exhibits sex differences. To examine the individual contribution of repressed viral infection, we took advantage of a transgenic model (Tg26) to investigate the contribution of HIV viral proteins to chronic inflammation and hypertension. A preliminary cytokine panel looking at 15 different cytokines found an increase in TNFα in male mice (P<0.05). Blood pressure (BP) measurements via radiotelemetry revealed increased mean arterial pressure (MAP: male: WT=112.3±1.3 vs Tg26=121.9±4.0 mmHg/ female: WT=110.6±3.01/ Tg26=120.3±6.9 mmHg) and heart rate (P<0.05) with preservation of diurnal variation in both sexes. Treatment with the TNFα inhibitor, etanercept, restored BP in Tg26 males only, reflecting the cytokine panel. Further investigation into vascular reactivity revealed endothelium-dependent dysfunction in both conduit and resistance vessels (P<0.05) with no impairment in vascular contractility in either sex. To test the contribution of immune cell derived viral proteins to cardiovascular disease, WT and Tg26 mice were submitted to bone marrow transplant (BMT) and vascular reactivity was assessed in resistance and conduit vessels. Tg26->WT BMT impaired endothelial relaxation (p<0.05), while WT->Tg26 BMT remarkably reversed the phenotype, suggesting a clear role of BM derived immune cells in the observed endothelial dysfunction. Investigation of immune cell subtypes led us to co-culture WT thoracic aortas in media of Tg26 Tcells, the primary target of HIV, for 16 hours which impaired endothelial relaxation when compared to aortas incubated in WT media. A cytokine panel of the media revealed a modest increase in TNFα levels (P=0.16) suggesting Tcells are a contributor to both impaired endothelium and increased TNFα. Further investigation into the source of endothelial dysfunction led us to investigate oxidative stress and the contribution of NADPH oxidases (NOX) and found only an increase in NOX1 expression in male (P<0.05) mice and a trend in females (P=0.06) when compared with NOX2 and NOX4. Additionally, an increase in NOX1 expression was found in Tg26->WT BMT in males (P=0.06) and females (P<0.05) which was restored to WT levels in WT->Tg26 BMT male mice. Inhibition of NOX1 utilizing the selective NOX1 inhibitor, GKT771, restored endothelial relaxation in Tg26->WT BMT in both vessel types and sexes showing a clear role of NOX1 in the observed endothelial impairment. Collectively, these data indicate that HIV-related hypertension involves immune regulated NOX1-dependent endothelial dysfunction in both sexes but TNFα-dependent mechanisms in males only providing evidence of sex specific mechanisms.

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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