Abstract
BackgroundApolipoprotein E-deficient (ApoE−/−) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE−/−-rat model.MethodsNormotensive, 8 weeks old ApoE−/− and Sprague–Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA).ResultsAfter 8 weeks, ApoE−/−-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE−/−-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN.ConclusionApoE−/−-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE−/−-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0914-9) contains supplementary material, which is available to authorized users.
Highlights
Apolipoprotein E-deficient (ApoE−/−) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans
Cardiac function, and metabolic parameters Eight weeks after renal denervation (RDN)-procedure, renal NE concentrations were significantly lower in SD-RDN and ApoE−/−RDN, when compared to their respective sham-operated controls (Fig. 1), confirming successful renal nerve ablation
Heart weight, systolic and diastolic blood pressure, heart rate, stroke volume, ejection fraction, left ventricular systolic, and diastolic volume did not differ between ApoE−/−-sham and SD-sham, demonstrating that at an age of 16 weeks ApoE−/−-rats remain normotensive
Summary
Apolipoprotein E-deficient (ApoE−/−) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE−/−-rat model. Hyperlipidemia can induce remodeling processes of the arterial wall, thereby impairing vascular compliance [2,3,4]. The underlying molecular mechanisms contributing to impaired vascular compliance are multifactorial and may involve increased sympathetic nerve activity leading to renin-angiotensin-aldosterone-system (RAAS). Renal denervation (RDN) has been shown to reduce blood pressure (BP) in animal models and in certain patients with uncontrolled hypertension [9,10,11,12]. Recent studies have demonstrated that RDN may exhibit additional systemic effects in parallel to BP lowering [13, 14], including improvement in arterial stiffness [15]. In normotensive ApoE-deficient mice, fed with Western-type diet, RDN attenuated atherosclerotic lesion formation at the aortic root without affecting hyperlipidemia [18]
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