Kang Lu, Hillestad Matthew L, Grande Joseph P, Croatt Anthony J, Barry Michael A, Farrugia Gianrico, Katusic Zvonimir S, Nath Karl A
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota;
Am J Physiol Heart Circ Physiol. 2015 Jun 1;308(11):H1402-13. doi: 10.1152/ajpheart.00882.2014. Epub 2015 Mar 27.
The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1(+/+) and HO-1(-/-) mice, whereas HO-1 induction was exaggerated in HO-2(-/-) mice compared with HO-2(+/+) mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.
本研究在部分颈动脉结扎诱导的病理性剪切应力的体内小鼠模型中检测了血红素加氧酶（HO）系统。在该模型中，随着血管病变相关基因的上调，HO-1在内皮细胞和外膜中被诱导表达，而HO-2主要在内皮细胞中上调。结扎后数分钟内，上调血管病变相关基因和HO-1的转录因子NF-κB被激活。HO-1或HO-2表达缺失会加剧颈动脉血流减少并加重血管损伤。动脉结扎后，HO-1(+/+)和HO-1(-/-)小鼠中HO-2的诱导情况相当，而与HO-2(+/+)小鼠相比，HO-2(-/-)小鼠中HO-1的诱导更为明显。腺相关病毒载体上调HO-1可增加血管HO-1表达和HO活性，并增加结扎侧和对侧颈动脉的血流量。急性抑制HO活性会降低结扎侧颈动脉的血流，而由一氧化碳释放分子-3递送的HO产物一氧化碳（CO）可增加颈动脉血流量。总之，在病理性剪切应力的部分颈动脉结扎模型中，本研究首次证明了1）HO-1和HO-2的上调及其血管保护作用以及CO的血管舒张作用，以及2）腺相关病毒载体在体内上调血管HO-1并伴随有益的血管反应。HO-1的诱导可能与NF-κB激活有关，并且与诱导的HO-2一起，HO-1的这种上调在体内病理性剪切应力中提供了一种抵消性的血管保护反应。
