With-no-lysine (K)-1 (WNK1) is the founding member of family of four protein kinases with atypical placement of catalytic lysine that play important roles in regulating epithelial ion transport. Gain-of-function mutations of WNK1 and WNK4 cause a mendelian hypertension and hyperkalemic disease. WNK1 is ubiquitously expressed and essential for embryonic angiogenesis in mice. Increasing evidence indicates the role of WNK kinases in tumorigenesis at least partly by stimulating tumor cell proliferation. Here, we show that human hepatoma cells xenotransplanted into zebrafish produced high levels of vascular endothelial growth factor (VEGF) and WNK1, and induced expression of zebrafish wnk1. Knockdown of wnk1 in zebrafish decreased tumor-induced ectopic vessel formation and inhibited tumor proliferation. Inhibition of WNK1 or its downstream kinases OSR1 (oxidative stress responsive kinase 1)/SPAK (Ste20-related proline alanine rich kinase) using chemical inhibitors decreased ectopic vessel formation as well as proliferation of xenotransplanted hepatoma cells. The effect of WNK and OSR1 inhibitors is greater than that achieved by inhibitor of VEGF signaling cascade. These inhibitors also effectively inhibited tumorigenesis in two separate transgenic zebrafish models of intestinal and hepatocellular carcinomas. Endothelial-specific overexpression of wnk1 enhanced tumorigenesis in transgenic carcinogenic fish, supporting endothelial cell-autonomous effect of WNK1 in tumor promotion. Thus, WNK1 can promote tumorigenesis by multiple effects that include stimulating tumor angiogenesis. Inhibition of WNK1 may be a potent anti-cancer therapy.

Brachial-ankle pulse wave velocity (baPWV) is used for predicting the severity of vascular damage and prognosis of atherosclerotic cardiovascular disease (ASCVD) in people with hypertension and diabetes mellitus. This correlation study aimed to compare the baPWV with other risk indicators for identification of subclinical vascular disease for primary prevention and to determine the clinical utility of baPWV-guided therapy in improving prognosis in high-risk subjects. We included 4881 subjects who underwent voluntary health examination at Mackay Memorial Hospital, Taiwan between 2014 and 2019. Participants were categorized into the low-risk (<5%), borderline-risk (5%–7.4%), intermediate-risk (7.5%–19.9%), and high-risk (≥20%) groups based on the 10-year risk for ASCVD. The predictive risk criteria, that is, the metabolic syndrome score, Framingham Risk Score, estimated glomerular filtration rate, and baPWV were compared among these groups. The chief cause of induced responses and the relationships between parameters were identified using principal component analysis. The participants’ ages, body mass index, systolic, diastolic blood pressure, triglycerides, fasting glucose, hemoglobin A1c, creatinine, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, metabolic syndrome, Framingham Risk Score, and age-related arterial stiffness (vascular age) increased significantly from the low-risk to high-risk groups (P < .001). The mean estimated glomerular filtration rate decreased significantly from the low- to high-risk groups (P < .001). The predicted vascular age and actual age differed significantly between the intermediate- and high-risk groups (P < .001). High-density lipoprotein levels plummeted significantly among the 4 groups (P < .001). The right and left baPWV and ankle brachial index differed significantly among the 4 groups (all P < .001) and increased from the low-risk to high-risk groups (P < .001). Carotid Doppler ultrasonography revealed a significant increase in plaque formation (23.5%, 35.4%, 46.3%, and 61.5% for the low-, borderline-, intermediate, and high-risk groups, respectively). The total explanatory variation was 61.9% for 2 principal variation factors (baPWV, 36.8% and creatinine, 25.1%). The vascular age predicted using baPWV greatly exceeded the chronological age. Plaque formation was significant even in the low-risk group, and its frequency increased with the predicted ASCVD risk. Risk indicators and baPWV are useful predictors of ASCVD, which in conjunction with conventional pharmacotherapy could be useful for primary prevention of plaque formation in subjects with cardiovascular comorbidities.