Zana Hassan Ibrahim
Raparin University, IraqPresentation Title:
Role of L-Arginine and tetrahydrobiopterin in attenuation of vascular Ang1-8 reactivity via endothelial PI3K/AKT/eNOS signaling pathways in HgCl2 pre-incubated rat aortic rings
Abstract
Background: Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality, often driven by endothelial dysfunction, inflammation, and oxidative stress. Environmental toxins such as heavy metals, particularly mercuric chloride (HgCl₂), have emerged as significant but underrecognized contributors to CVD pathogenesis. HgCl₂ impairs vascular function by elevating reactive oxygen species (ROS), reducing nitric oxide (NO) bioavailability, and disrupting renin–angiotensin system (RAS) homeostasis. Tetrahydrobiopterin (BH₄) and L-arginine (LA) - critical for endothelial NO synthase (eNOS) function - are known to support endothelial integrity. However, their combined vascular protective effects, especially in the context of mercury-induced oxidative stress and RAS dysregulation, remain to be fully elucidated.
Objective: To investigate the individual and combined effects of L-arginine and BH₄ on Ang II-induced vascular responses in HgCl₂-preincubated rat aortic rings, with a specific focus on AT₁, AT₂, and ACE2 pathways.
Methods: Thoracic aortic rings from male rats were incubated with HgCl₂ (1 μM, 45 min) to induce vascular injury. Dose–response curves to Ang II were generated in the presence or absence of HgCl₂, LA, BH₄, and their combination. Pharmacological inhibition of AT₁ (valsartan), AT₂ (PD123319), and ACE2 (MLN-4760) receptors was used to explore mechanistic contributions. Endothelial integrity was validated by acetylcholine-induced relaxation.
Results: HgCl₂ exposure markedly reduced Ang II-induced contraction, lowering Emax, pD₂, and AUC. LA and BH₄ monotherapies partially restored vascular responses, while their combination yielded synergistic improvements in Emax and pD₂, consistent with enhanced eNOS recoupling and NO restoration. Interestingly, LA alone significantly improved AUC, suggesting substrate limitation under oxidative stress. AT₁ blockade completely abolished Ang II responses, confirming AT₁ dependency, whereas AT₂ or ACE2 inhibition intensified vasoconstriction - both effects reversed by LA and BH₄ co-treatment.
Conclusion: Combined supplementation with L-arginine and BH₄ effectively counteracts mercury-induced vascular dysfunction by restoring NO bioavailability and modulating Ang II receptor signaling, particularly through the AT₁/AT₂/ACE2 axis. These findings provide novel insight into therapeutic strategies targeting eNOS cofactor-substrate synergy to mitigate environmental toxin-related vascular injury and CVD risk.
Biography
Zana Hassan Ibrahim completed his master’s degree in Physiology in 2017. He is currently a PhD student at the University of Sulaimani, Iraq. He also serves as the head of the Quality Assurance Office at Raparin University, Iraq. He has over six publications with numerous citations and has served as a lecturer at four different universities.
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