Role of proinflammatory cytokines and redox homeostasis in exercise-induced delayed progression of hypertension in spontaneously hypertensive rats

Abstract

Hypertension is a well-known risk factor for various cardiovascular diseases. Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients. However, the precise mechanisms of exercise training (ExT)-induced effects on the development of hypertension are poorly understood. Therefore, we hypothesized that chronic ExT would delay the progression of hypertension in young spontaneously hypertensive rats (SHRs). In addition, we explored whether the beneficial effects of chronic ExT were mediated by reduced proinflammatory cytokines and improved redox status. We also investigated the involvement of nuclear factor-kappaB in exercise-induced effects. To test our hypotheses, young normotensive (Wistar-Kyoto) and SHRs were given moderate-intensity ExT for 16 weeks. Blood pressure was determined by the tail-cuff method, and cardiac function was assessed by echocardiography. Myocardial total reactive oxygen species and superoxide production were measured by electron paramagnetic resonance spectroscopy; tumor necrosis factor-alpha, interleukin-1beta, gp91(phox), and inducible NO synthase by real-time PCR; and nuclear factor kappaB activity by electrophoretic mobility shift assay. Chronic ExT in hypertensive rats resulted in significantly reduced blood pressure, reduced concentric hypertrophy, and improved diastolic function. ExT significantly reduced proinflammatory cytokines and inducible NO synthase, attenuated total reactive oxygen species and superoxide production, and increased antioxidants in SHRs. ExT also resulted in increased NO production and decreased nuclear factor kappaB activity in SHRs. In summary, chronic ExT delays the progression of hypertension and improves cardiac function in young SHRs; these ExT-induced beneficial effects are mediated by reduced proinflammatory cytokines and improved redox homeostasis via downregulation of nuclear factor-kappaB.

Figure 1

Time course of blood pressure (mmHg) in WK and SHR rats. a) Systolic blood pressure (SBP); b) diastolic blood pressure (DBP); c) mean arterial pressure (MAP). BP was significantly reduced in SHRex compared to SHRsed from 8 weeks of exercise (arrow). Values are means±SE. n=10 in each group. *p<0.05 WKsed vs SHRsed; ^†p<0.05 SHRsed vs SHRex.

Figure 2

Effects of exercise training on LV pro-inflammatory cytokines (PICs) in WK and SHR rats. a) mRNA expression of TNF-α; b) mRNA expression of IL-1β; c) a representative western blot; d) densitometric analysis of protein expression. Values are means±SE. n=6–8 in each group. *p<0.05 WKsed vs SHRsed; ^†p<0.05 SHRsed vs SHRex.

Figure 3

Effects of exercise training on LV free radical production in WK and SHR rats. a) Total reactive oxygen species; b) superoxide; c) peroxynitrite. Values are means±SE. n=10 in each group. *p<0.05 WKsed vs SHRsed; ^†p<0.05 SHRsed vs SHRex.

Figure 4

Effects of exercise on gp91^phox, and iNOS expression in the LV of WK and SHR rats. a) mRNA expression of gp91^phox; b) a representative western blot; c) densitometric analysis of protein expression; d) mRNA expression of iNOS. Values are means±SE. n=6 in each group. *p<0.05 WKsed vs SHRsed; ^†p<0.05 SHRsed vs SHRex.

Figure 5

Effects of exercise on LV NF-κB binding activity in WK and SHR rats. a) Representative EMSA results of NF-κB binding activity; b) densitometric analysis of NF-κB binding intensity (mean±SE). Values are means±SE. n=6 in each group. *p<0.05 WKsed vs SHRsed; ^†p<0.05 SHRsed vs SHRex.