Tiwari Shuchita, Ndisang Joseph Fomusi
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Curr Pharm Des. 2014;20(9):1354-69. doi: 10.2174/13816128113199990558.
Hypertension is a complex interplay of interrelated etiologies, and the leading risk factor for many cardiovascular morbidity and mortality worldwide. Cardinal pathophysiological features of hypertension include enhanced vascular inflammation, vascular remodeling, vascular contractility and increased oxidative stress. In response to oxidative, inflammatory or other noxious stimuli, many physiological pathways like the heme oxygenase (HO) system are activated in an attempt to counteract tissue insults. However, the pathophysiological activation of the HO system only results to a transient increase of HO activity that fall below the necessary threshold capable of activating the downstream signaling components of the HO system like the soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) secondary messenger system. Therefore, a more robust potentiation of the HO system by pharmacological agents such as hemin, heme-arginate, cobalt protoporphyrin or through retroviral HO-1 gene delivery would be needed to surmount the threshold for cytoprotection. The HO system modulates cellular homeostasis. Importantly, the HO system plays a vital role in a wide spectrum of physiologic including the regulation of blood vessel tone. Alterations in the activity and expression of HO has been correlated to pathophysiology of hypertension and related complications such as hypertrophy, myocardial infarction and heart failure. Moreover, the cytoprotection exerted by HO is attributable to its catabolic products namely, carbon monoxide, bilirubin/biliverdin, and ferritin that are known to modulate immune, inflammatory and oxidative insults. The growing incidence of hypertension and associated cardiometabolic complications has prompted the need for the exploration of alternative therapeutic strategies like substances capable of potentiating the HO system. This review briefly, highlights the functional significance of the HO system and its downstream signaling molecules including bilirubin/biliverdin, carbon monoxide and ferritin as potential therapeutic modalities for the management of hypertension and its related co-morbid conditions.
高血压是多种相互关联病因的复杂相互作用，是全球许多心血管疾病发病和死亡的主要危险因素。高血压的主要病理生理特征包括血管炎症增强、血管重塑、血管收缩性增加以及氧化应激增强。针对氧化、炎症或其他有害刺激，许多生理途径如血红素加氧酶（HO）系统会被激活，试图抵消组织损伤。然而，HO系统的病理生理激活仅导致HO活性短暂增加，低于激活HO系统下游信号成分如可溶性鸟苷酸环化酶（sGC）/环磷酸鸟苷（cGMP）第二信使系统所需的阈值。因此，需要通过诸如血红素、血红素精氨酸、钴原卟啉等药物或通过逆转录病毒HO-1基因递送对HO系统进行更强有力的增强，以克服细胞保护的阈值。HO系统调节细胞内稳态。重要的是，HO系统在广泛的生理过程中发挥着至关重要的作用，包括血管张力的调节。HO活性和表达的改变与高血压的病理生理学以及相关并发症如肥大、心肌梗死和心力衰竭相关。此外，HO发挥的细胞保护作用归因于其分解代谢产物，即一氧化碳、胆红素/胆绿素和铁蛋白，已知这些产物可调节免疫、炎症和氧化损伤。高血压及相关心脏代谢并发症发病率的不断上升促使人们需要探索替代治疗策略，如能够增强HO系统的物质。本综述简要强调了HO系统及其下游信号分子（包括胆红素/胆绿素、一氧化碳和铁蛋白）作为高血压及其相关合并症潜在治疗方式的功能意义。
