DelloStritto Daniel J, Connell Patrick J, Dick Gregory M, Fancher Ibra S, Klarich Brittany, Fahmy Joseph N, Kang Patrick T, Chen Yeong-Renn, Damron Derek S, Thodeti Charles K, Bratz Ian N
Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
California Medical Innovations Institute, San Diego, CA, 92121, USA.
Basic Res Cardiol. 2016 Mar;111(2):21. doi: 10.1007/s00395-016-0539-4. Epub 2016 Feb 24.
We demonstrated previously that TRPV1-dependent coupling of coronary blood flow (CBF) to metabolism is disrupted in diabetes. A critical amount of H2O2 contributes to CBF regulation; however, excessive H2O2 impairs responses. We sought to determine the extent to which differential regulation of TRPV1 by H2O2 modulates CBF and vascular reactivity in diabetes. We used contrast echocardiography to study TRPV1 knockout (V1KO), db/db diabetic, and wild type C57BKS/J (WT) mice. H2O2 dose-dependently increased CBF in WT mice, a response blocked by the TRPV1 antagonist SB366791. H2O2-induced vasodilation was significantly inhibited in db/db and V1KO mice. H2O2 caused robust SB366791-sensitive dilation in WT coronary microvessels; however, this response was attenuated in vessels from db/db and V1KO mice, suggesting H2O2-induced vasodilation occurs, in part, via TRPV1. Acute H2O2 exposure potentiated capsaicin-induced CBF responses and capsaicin-mediated vasodilation in WT mice, whereas prolonged luminal H2O2 exposure blunted capsaicin-induced vasodilation. Electrophysiology studies re-confirms acute H2O2 exposure activated TRPV1 in HEK293A and bovine aortic endothelial cells while establishing that H2O2 potentiate capsaicin-activated TRPV1 currents, whereas prolonged H2O2 exposure attenuated TRPV1 currents. Verification of H2O2-mediated activation of intrinsic TRPV1 specific currents were found in isolated mouse coronary endothelial cells from WT mice and decreased in endothelial cells from V1KO mice. These data suggest prolonged H2O2 exposure impairs TRPV1-dependent coronary vascular signaling. This may contribute to microvascular dysfunction and tissue perfusion deficits characteristic of diabetes.
我们之前证明，在糖尿病状态下，冠状动脉血流（CBF）与代谢之间依赖瞬时受体电位香草酸亚型1（TRPV1）的偶联被破坏。一定量的过氧化氢（H2O2）有助于CBF调节；然而，过量的H2O2会损害反应。我们试图确定H2O2对TRPV1的差异调节在多大程度上调节糖尿病患者的CBF和血管反应性。我们使用对比超声心动图研究TRPV1基因敲除（V1KO）小鼠、db/db糖尿病小鼠和野生型C57BKS/J（WT）小鼠。H2O2以剂量依赖方式增加WT小鼠的CBF，这一反应被TRPV1拮抗剂SB366791阻断。在db/db和V1KO小鼠中，H2O2诱导的血管舒张明显受到抑制。H2O2在WT冠状动脉微血管中引起强大的对SB366791敏感的舒张；然而，在db/db和V1KO小鼠的血管中，这种反应减弱，表明H2O2诱导的血管舒张部分通过TRPV1发生。急性暴露于H2O2可增强WT小鼠中辣椒素诱导的CBF反应和辣椒素介导的血管舒张，而长时间管腔内暴露于H2O2会减弱辣椒素诱导的血管舒张。电生理学研究再次证实，急性暴露于H2O2可激活HEK293A细胞和牛主动脉内皮细胞中的TRPV1，同时确定H2O2增强辣椒素激活的TRPV1电流，而长时间暴露于H2O2会减弱TRPV1电流。在WT小鼠分离的冠状动脉内皮细胞中发现了H2O2介导的内源性TRPV1特异性电流激活的证据，而在V1KO小鼠的内皮细胞中这种电流减少。这些数据表明，长时间暴露于H2O2会损害依赖TRPV1的冠状动脉血管信号传导。这可能导致糖尿病特有的微血管功能障碍和组织灌注不足。
