Natriuretic peptides in the cross-talk of human cardiovascular and metabolic regulation

Most patients with arterial hypertension are overweight or obese. Obese patients require more antihypertensive medications to have their blood pressure controlled. In fact, obesity is an important risk factor for treatment-resistant arterial hypertension. Moreover, hypertension and obesity are additive in terms of cardiovascular and metabolic risk. These issues have recently been reviewed in this Journal [1]. Coexistence of arterial hypertension and obesity suggest that there is a cross-talk between metabolic and cardiovascular organs. Much of the research in recent years has focused on how obesity promotes arterial hypertension. Yet, the cross-talk is bidirectional such that signals generated in cardiovascular organs also affect metabolism. Natriuretic peptides appear to be particularly important in this regard [2]. Unlike arterial hypertension in lean individuals, volume expansion and increased cardiac output are believed to mediate obesity-associated hypertension. Neurohumoral mechanisms with over-activity of both sympathetic nervous system and renin–angiotensin system have also been implicated [3]. This appears to be the case also for metabolic mechanisms, since elevated plasma levels of insulin may trigger a sympathetic activation [4]. Elegant studies in animals suggest that signalling molecules produced in adipose tissue, particularly leptin, may increase sympathetic activity and blood pressure through the hypothalamic–melanocortin pathway. Observations in rare patients with genetic leptin [5] or brain melanocortin 4 receptor deficiency [6] translated these findings from animals to humans. However, the study by Bonfils et al.[7] in this issue reminds us that obesity-associated arterial hypertension cannot be explained by a single mechanism. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are released from cardiac atria and ventricles, respectively. Both peptides are produced as pre-prohormone and are stored as prohomones in intracellular granules. Once released, natriuretic peptides raise renal sodium excretion, elicit vasodilation and are physiological renin–angiotensin system opponents. The response is primarily mediated by the guanylyl cyclase-coupled natriuretic peptide receptor (NPR)-A. NPR-C, which is sometimes referred to as scavenger receptor, is devoid of guanylyl cyclase activity and facilitates cellular natriuretic peptide uptake and degradation. In addition, natriuretic peptides are enzymatically cleaved by neprilysin. Because volume loading and increased cardiac output augment natriuretic peptide release, one would expect to observe increased natriuretic peptide levels in obesity, particularly in obese hypertensive individuals. Instead, circulating ANP is paradoxically decreased in obese normotensive individuals and more so in obese hypertensive patients [8]. Furthermore, sodium loading increases circulating ANP levels less in obese compared with lean patients [9]. Paradoxical natriuretic peptide deficiency in obesity has been confirmed in large epidemiological surveys [10]. Reductions in natriuretic peptide availability could result from decreased release and/or excess clearance. The observation that NPR-C [8] and neprilysin [11] are up-regulated in human obesity is consistent with increased clearance mechanisms. Conversely, fasting reduces NPR-C expression in rats [12]. Reduced cardiac ANP gene expression in obese Zucker rats [13] suggests that natriuretic peptide release may be affected as well. As ANP is cleavage from its precursor pro-ANP, mid-regional (mR)-proANP is released in equimolar amounts. Unlike ANP, mR-proANP is not cleared through receptor-mediated endocytosis or enzymatic degradation and can, therefore, serve as ANP release biomarker. Bonfils et al. assessed mR-proANP levels in normotensive and hypertensive severely obese patients before and following substantial weight reduction through gastric bypass surgery. The fact that patients were tested on a lower and on a higher sodium diet is a particular strength of the study. At follow-up, hypertensive and normotensive patients had lost approximately 16% of their initial body weight with concomitant improvement in glucose metabolism and glomerular hyper-filtration. Blood pressure and heart rate were reduced in the hypertensive subgroup. Cardiac output tended to decrease. The observations that plasma and blood volume did not decrease and that sodium sensitivity was largely unchanged following weight loss challenge current pathophysiological concepts regarding obesity-associated arterial hypertension. In the hypertensive subgroup, mR-proANP was significantly increased following weight loss, regardless of sodium intake. In the normotensive subgroup, mR-proANP remained unchanged. This observation suggests that weight loss may improve blood pressure in part by increasing natriuretic peptide release, and highlights the importance of natriuretic peptides in the pathogenesis of obesity-associated hypertension. The entire picture, however, is made more complex by the recent observation by our group in Milan that sleeve gastrectomy – another technique for surgical weight management – attenuates sympathetic activity [14]. It is tempting to speculate that improved natriuretic peptide signalling contributes to the response. At least in heart failure patients, natriuretic peptides have been shown to modulate sympathetic activity [15]. Recent studies suggest that natriuretic peptides also regulate lipid and glucose metabolism, thus providing a mechanistic link between cardiovascular and metabolic disease. In epidemiological studies, reduced circulating mR-proANP concentrations heralded increased risk for type 2 diabetes mellitus [16]. In adipose tissue, natriuretic peptides potently stimulate lipolysis and elicit adiponectin release [17–19]. ANP also increases postprandial fat oxidation [20]. Chronically, natriuretic peptides induce thermogenic gene expression programmes and augment oxidative capacity in adipose tissue and in skeletal muscle [21]. Through these actions, natriuretic peptides protect animals fed a high caloric high fat diet from weight gain and insulin resistance [22]. Given their cardiovascular and in metabolic actions, mechanisms regulating natriuretic peptide availability and signalling deserve our attention. Common variants in the genes encoding ANP and BNP affect their circulating levels [23]. Recently, the microRNA miR-425 was shown to negatively regulate ANP production and a common genetic variant makes ANP production resistant to miR-425 [24]. Post-translational proBNP modification appears to regulate BNP release [25]. Finally, glucagon-like peptide 1 receptors expressed in cardiac atria promote ANP release [26]. It is tempting to speculate that all these mechanisms could affect the susceptibility to obesity-associated arterial hypertension. The tight link between cardiovascular and metabolic disease through natriuretic peptides could have therapeutic implications, which may not be limited to obesity-associated arterial hypertension. In particular, treatments improving natriuretic peptide availability or signalling could address cardiovascular as well as metabolic ailments. Weight loss and physical exercise may mediate some of their beneficial actions through natriuretic peptides. New pharmacological approaches are on the horizon. Endogenous natriuretic peptide levels can be augmented through neprilysin inhibition. A combined neprilysin angiotensin receptor inhibitor ameliorated blood pressure in hypertensive patients [27] and reduced the risk of death and of hospitalizations in heart failure patients [28]. Studies testing metabolic responses to this treatment are ongoing (www.clinicaltrials.com; NCT01631864). Engineered natriuretic peptides have been tested in preclinical studies [29]. The natriuretic peptide-induced cyclic guanosine monophosphate signal could also be amplified through phosphodiesterase-5 inhibition. We strongly believe that these approaches should be tested in obese hypertensive patients whose metabolic and cardiovascular risk may not be sufficiently controlled with current treatments. In fact, some antihypertensive medications, particularly beta-adrenoreceptor blockers and diuretics, may further promote adiposity and/or insulin resistance. ACKNOWLEDGEMENTS Conflicts of interest J.J. is the scientific advisor for Novartis, Boehringer-Ingelheim, Orexigen, Riemser and Vivus.