Abstract
Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice.Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR.Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5–7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = −0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2).Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients.
Highlights
The baseline body weight, systolic, diastolic and mean blood pressure, and the heart rate were similar in the sham surgery and the Renal denervation (RDN) groups (P > 0.05, Table 2)
The norepinephrine in the kidney at the end of the main experiment was lower in the RDN group compared with sham surgery group (P = 0.005, Figure 2B)
This study focussed on assessing the effect of RDN on atherosclerosis severity in a mouse model
Summary
Renal denervation (RDN) is used in clinical practice to lower blood pressure in treatment-resistant hypertension (Krum et al, 2009; Esler et al, 2010; Worthley et al, 2013; Bhatt et al, 2014; Papademetriou et al, 2014) by inhibiting the sympathetic outflow from the brain (Schlaich et al, 2009). The effects of RDN on atherosclerosis in mouse models that have hypertension has not been investigated. This is important since RDN is performed in hypertensive patients. This study was designed to investigate whether RDN affects atherosclerosis severity in hypertensive ApoE−/− mice infused with angiotensin II. As angiotensin II infusion induces aortic aneurysm we assessed the effect of RDN on aortic aneurysm severity
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