Translational Medicine in Uremic Vascular Calcification: Scavenging ROS Attenuates p-Cresyl Sulfate-Activated Caspase-1, NLRP3 Inflammasome and Eicosanoid Inflammation in Human Arterial Smooth Muscle Cells

Life

Chih-Ping Hsu¹  Chang-Chin Wu²  Ting-Ming Wang³  Jia-Feng Chang⁴  Chih-Yu Hsieh⁴  Kuo-Chin Hung⁵  Kuo-Cheng Lu⁶  Shih-Hao Liu⁷  Hsiao-Ling Kuo⁸  Wei-Ning Lin⁹  Chi-Feng Hung^1,10  Wen-Chin Ko^1,10 

[1] Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan;Department of Orthopaedic Surgery, En Chu Kong Hospital, New Taipei City 237, Taiwan;Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei 100, Taiwan;Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan;Division of Nephrology, Department of Medicine, Min-Sheng General Hospital, Taoyuan City 330, Taiwan;Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan;Division of Pathology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan;Division of Rheumatology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan;Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan;School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan;

关键词: Caspase-1;    COX2;    cPLA2;    IL-1β;    inflammasome;    NLRP3;   

DOI  :  10.3390/life12050769

来源: DOAJ

【 摘 要 】

We formerly proved that uremic vascular calcification (UVC) correlates tightly with oxidative elastic lamina (EL) injury and two cell fates (apoptosis and osteocytic conversion) in smooth muscle cells (SMC) of chronic kidney disease (CKD) patients and eliminating p-cresyl sulfate (PCS)-activated intracellular ROS ameliorates the MAPK signaling pathway in a human arterial SMC (HASMC) model. Nonetheless, whether ROS scavenger attenuates PCS-triggered inflammasome activation and eicosanoid inflammation in the UVC process remains unknown. Patients with lower extremity amputation were categorized into CKD and normal control group according to renal function. We used immunohistochemistry stain to analyze UVC in arterial specimens, including oxidative injury (8-hydroxy-2′-deoxyguanosine (8-OHdG) and internal EL disruption), cytosolic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX2), interleukin-1 beta (IL-1β), caspase-1 and NLRP3. To simulate the patho-mechanism of human UVC, the therapeutic effects of ROS scavenger on PCS-triggered inflammatory pathways was explored in a HASMC model. We found CKD patients had higher circulating levels of PCS and an increase in medial arterial calcification than the control group. In CKD arteries, the severity of UVC corresponded with expressions of oxidative EL disruption and 8-OHdG. Furthermore, coupling expressions of cPLA2 and COX2 were accentuated in CKD arteries, indicative of eicosanoid inflammation. Notably, tissue expressions of IL-1β, caspase-1 and NLRP3 were enhanced in parallel with UVC severity, indicative of inflammasome activation. From bedside to bench, ROS scavenger attenuates PCS-activated expressions of cPLA2/COX2, pro-caspase-1 and NLRP3 in the HASMC model. UVC as an inevitable outcome is predictive of death in CKD patients. Nonetheless, UVC remain pharmacoresistant despite the evolution of treatment for mineral-parathyroid hormone-vitamin D axis. Beyond the mineral dysregulation, the stimulation of pro-oxidant PCS alone results in eicosanoid inflammation and inflammasome activation. Concerning the key role of Caspase-1 in pyroptosis, cell fates of HASMC in uremic milieu are not limited to apoptosis and osteogenesis. In view of this, reducing ROS and PCS may act as a therapeutic strategy for UVC-related cardiovascular events in CKD patients.

【 授权许可】

Unknown