Alteration of the IL-33-sST2 pathway in hypertensive patients and a mouse model

Abstract

Inflammatory cells play an important role in the occurrence of hypertension. Recent studies have demonstrated that interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signaling plays a critical role in the pathogenesis of several cardiovascular diseases. We aimed to evaluate the association of IL-33 and its receptor levels with the occurrence of hypertension in angiotensin II (Ang II)-infused mice using microarray analysis and validated our results in human specimens. Male wild-type mice were infused with Ang II (1500 ng/kg/min) for 1, 3 and 7 days. Patients with essential hypertension (EH) (n = 166) and healthy control subjects (n = 306) were enrolled. Levels of IL-33 and ST2 mRNAs in serum and peripheral blood mononuclear cells (PBMCs) were analyzed by Luminex assay or ELISA and qPCR analysis. We found that IL-33 expression was significantly increased in the aortas of mice receiving Ang II infusion compared with that of control mice. In contrast, the levels of IL-33 in serum and PBMCs were not significantly different between hypertensive patients and normal controls. However, the levels of soluble ST2 (sST2) in serum and PBMCs were markedly higher in hypertensive patients than in controls (P < 0.001 and P = 0.014, respectively). In addition, the ST2L level in PBMCs was also significantly decreased in hypertensive patients (P = 0.028). Further, logistic analysis showed that the odds ratios of having hypertension based on sST2 levels in serum and PBMCs were 9.714 and 2.244 (P = 0.013 and P = 0.024, respectively) compared with the control group. Above all, sST2 acted as a risk factor for the occurrence of hypertension and may be a promising novel predictive marker for EH.

Keywords: Hypertension; IL-33; Peripheral blood mononuclear cells; ST2L; sST2.

Fig. 1

Increased levels of IL-33 mRNA in aortic tissues in an Ang II-induced hypertension model by subcutaneous infusion of Ang II as shown by microarray analysis and qPCR analysis. a Relative IL-33 mRNA levels in microarray analysis. The abscissa coordinates were the control group, Ang II infusion for 1 day, Ang II infusion for 3 days and Ang II infusion for 7 days. The ordinate was the relative expression levels of IL-33 mRNAs in the microarray analysis. b Relative IL-33 mRNA levels in qPCR analysis. The abscissa coordinates were the control group, Ang II infusion for 1 day, Ang II infusion for 3 days and Ang II infusion for 7 days. The ordinate was the relative expression levels of IL-33 mRNAs in qPCR analysis. **P < 0.01 compared to control. qPCR quantitative real-time polymerase chain reaction

Fig. 2

Levels of IL-33 and sST2 in serum in hypertensive patients and control groups. Data are represented as the median (IQR). a Luminex assay showed that there was no significant difference in serum IL-33 levels between hypertensive patients and controls (median: 108.34 ng/ml and 109.65 ng/ml, P = 0.141). b ELISA indicated that sST2 levels were markedly elevated in hypertensive patients compared to normal controls (median: 663.84 vs 549.05 ng/mL, P < 0.001). IQR interquartile range

Fig. 3

Levels of IL-33, sST2 and ST2L mRNAs in PBMCs in hypertensive patients and control groups. Data are represented as the median (IQR). a There was no significant difference in IL-33 mRNA levels between hypertensive patients and normal controls (median: 0.75 vs 0.71; P = 0.243). b mRNA levels were significantly increased in hypertensive patients compared to normal controls (median: 1.32 vs 0.92; P = 0.014). c ST2L mRNA levels were markedly decreased in hypertensive patients compared to normal controls (median: 0.78 vs 1.12; P = 0.028)