Glycosylation of natriuretic peptides in obese heart failure: mechanistic insights

Abstract

Comment on: Lewis LK, Raudsepp SD, Prickett TCR, et al. ProBNP that is not glycosylated at threonine 71 is decreased with obesity in patients with heart failure. Natriuretic peptides (NPs) are cardiac derived hormones that are secreted in response to increased wall stress, stretching of the myocardium, volume overload, and angiotensin II stimulation. The principal circulating NPs, atrial and B-type NP (ANP and BNP respectively) are released as precursor molecules (proANP and proBNP) which are processed to active components ANP and BNP, and inactive amino-terminal fragments NT-proANP and NT-proBNP (1). Mature NPs bind and activate membrane receptors called NP receptor A and B (signaling receptor), which results in increased glomerular filtration, sodium excretion, vasodilation, and direct inhibition of the renin-angiotensin-aldosterone system. Mature NPs are removed from the circulation by proteolysis by an enzyme called neprilysin and via NP receptor C (clearance receptor) (2). In states of volume and pressure overload such as heart failure, there is an increased concentration of NPs in circulation, which has led to their use as diagnostic and prognostic markers for heart failure. BNP and its related peptides have greater in-vitro stability and better diagnostic utility compared to ANP. Therefore, BNP and its fragments (proBNP and NT-proBNP) emerged as ideal candidates for assessment and subsequently became established as gold-standard biomarkers for the risk assessment, diagnosis, prognostication, and treatment monitoring of heart failure (3,4). Obesity and NPs Under normal physiological conditions, biological variability of NP levels has been described with body mass index (BMI) (5), in addition to age, sex (5), race (5-7), and glomerular filtration rate (5) contributing to the inter-and intra-individual differences in NP levels. This variability persists in the disease state of heart failure. Several population-based studies have shown that there is an inverse association of BMI with NP levels (8,9), with obese individuals having 30-40% lower NP levels compared with lean individuals. Obesity is well recognized as a NP deficient state (5) and an important contributor to the etiopathogenesis of heart failure. Accurate clinical assessment of heart failure is difficult in obese individuals (10,11) which underlines the significance of accurately measuring these biomarkers using appropriate assays, as demonstrated by Lewis et al. (12). ProBNP not glycosylated at Thr71 (NG-Thr71) is a surrogate for proBNP processing In response to stimulus, the BNP gene (NPPB) is transcribed and translated into 134-amino acid pre-proBNP, which is converted to prohormone (proBNP 1-108). After synthesis, proBNP undergoes post-translational modification before being released into the circulation. The