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<p>This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60&#xa0;mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H<sub>2</sub>O<sub>2</sub> scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H<sub>2</sub>O<sub>2</sub>-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H<sub>2</sub>O<sub>2</sub> significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H<sub>2</sub>O<sub>2</sub>-mediated response. In CAD, the contribution of both NO and H<sub>2</sub>O<sub>2</sub> is diminished, while an NO/H<sub>2</sub>O<sub>2</sub>-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.</p>

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The role of NO, H2O2, and non-NO/H2O2 mechanisms in acetylcholine (ACh)-induced dilation of human arterioles in the absence and presence of coronary artery disease

  • 期刊论文

  • 发表日期：

    2025年11月1日

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  • Kostiantyn Drachuk,
  • Yoshinori Nishijima,
  • Aravind Parthasarathy,
  • Yangjing Xie,
  • Sneha Nagavally,
  • Aprill Dawson,
  • David D. Gutterman,
  • David X. Zhang

摘要

This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60 mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H2O2 scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H2O2-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H2O2 significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H2O2-mediated response. In CAD, the contribution of both NO and H2O2 is diminished, while an NO/H2O2-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.