Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure

Abstract

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258±2,078 units) than in both sham groups (11,709±4,169 and 8,998±4,823 units); this decrease was significantly prevented by renal denervation (8,190±3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

“…Moreover, sympathetic nerve activity in patients after renal transplantation was only normalized with concomitant bilateral nephrectomy (17). Additional work in experimental models indicated (21,23) that efferent neurogenic influences on cardiac pathology in renal insufficiency are mediated by renal afferent nerve activity (1).…”

The effect of uraemia on the duration of arrhythmias in the context of cardioprotective ischaemic conditioning strategies

“…However this four-week model has been shown to develop hypertension,25 34 LVH,34 35 a reduced fractional shortening on echocardiography,36 impaired cardiac function secondary to bioenergetic failure,35 capillary rarefaction and myocardial interstitial cell proliferation37 leading to reduced ischaemia tolerance 25 34. Additionally even if the SNx model did not represent a severe uraemic phenotype, it is known that even mild to moderate CKD leads to a huge burden of cardiovascular disease: results from the HOPE study indicate that patients with moderate CKD (serum creatinine 125–200 μmol/L) had a 40% increase in sudden cardiac death when compared with individuals with normal renal function,,38 that patients with CKD stage 3 had an OR for cardiovascular events, of two to four compared patients with normal renal function and up to 40% of patients presenting with a myocardial infarction have mild to moderate renal failure 39…”

Reversing gene expression in cardiovascular target organs following chronic depression of the paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in spontaneous hypertensive rats

“…The beneficial effect of sympathetic downregulation and/or blood pressure decrease on cardiac structure and renal function is well established (Amann K, 2011;Weinberg E, 1997;Bautista R, 2001;Li Y, 2010).…”