Nesfatin-1 as a novel cardiac peptide: identification, functional characterization, and protection against ischemia/reperfusion injury

Abstract

Nesfatin-1 is an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide. It controls feeding behavior, water intake, and glucose homeostasis. If intracerebrally administered, it induces hypertension, thus suggesting a role in central cardiovascular control. However, it is not known whether it is able to directly control heart performance. We aimed to verify the hypothesis that, as in the case of other hypothalamic satiety peptides, Nesfatin-1 acts as a peripheral cardiac modulator. By western blotting and QT-PCR, we identified the presence of both Nesfatin-1 protein and NUCB2 mRNA in rat cardiac extracts. On isolated and Langendorff-perfused rat heart preparations, we found that exogenous Nesfatin-1 depresses contractility and relaxation without affecting coronary motility. These effects did not involve Nitric oxide, but recruited the particulate guanylate cyclase (pGC) known as natriuretic peptide receptor A (NPR-A), protein kinase G (PKG) and extracellular signal-regulated kinases1/2 (ERK1/2). Co-immunoprecipitation and bioinformatic analyses supported an interaction between Nesfatin-1 and NPR-A. Lastly, we preliminarily observed, through post-conditioning experiments, that Nesfatin-1 protects against ischemia/reperfusion (I/R) injury by reducing infarct size, lactate dehydrogenase release, and postischemic contracture. This protection involves multiple prosurvival kinases such as PKCε, ERK1/2, signal transducer and activator of transcription 3, and mitochondrial K(ATP) channels. It also ameliorates contractility recovery. Our data indicate that: (1) the heart expresses Nesfatin-1, (2) Nesfatin-1 directly affects myocardial performance, possibly involving pGC-linked NPR-A, the pGC/PKG pathway, and ERK1/2, (3) the peptide protects the heart against I/R injury. Results pave the way to include Nesfatin-1 in the neuroendocrine modulators of the cardiac function, also encouraging the clarification of its clinical potential in the presence of nutrition-dependent physio-pathologic cardiovascular diseases.

The innovative “Bio-Oil Spread” prevents metabolic disorders and mediates preconditioning-like cardioprotection in rats

“…Here we observed that, compared to HFD-fed rats, cardioprotection induced by SD diet increased the expression of p-Akt and p-ERK. This agrees with the involvement of these kinases in ischemic pharmacological cardioprotection and Post-C maneuvers [45,46]. In line with an SD-associated protective role, the heart of SD-fed rats showed an increased expression of the anti-apoptotic protein Bcl-2 which correlates with the reduction of IS.…”

Rs214101 Variation of NUCB2/Nesfatin-1 Gene: Effects on Metabolic Parameters Independent of Type 2 Diabetes or Obesity in Coronary Artery Disease

“…Sahin et al reported that Nesfatin-1 levels play an important role in the pathogenesis of hypertension in patients with polycystic ovary syndrome (18). Angelone et al demonstrated that Nesfatin-1 elicits an incisive influence on the heart by depressing contractility and relaxation (23). Based on mentioned above findings NUCB2/Nesfatin-1 involved in energy homeostasis and atherosclerosis pathogenesis, it can be a candidate gene affecting the development of CAD.…”

Possible Activation of the Immune System by Chronic Peripheral Nesfatin-1 Application at the Acute Phase of Ischemia/Reperfusion Injury

“…Angelone et al (16) suggested that nesfatin-1 protects the heart against I/R injury by reducing infarct size and releasing lactate dehydrogenase as well as by post-ischemic contracture. Özsavci et al (17) reported that nesfatin-1 exerted a neuroprotective effect in subarachnoid hemorrhage-induced injury in rats by inhibiting neutrophil infiltration and the subsequent release of inflammatory mediators.…”

“…It is suggested that there is a link between nesfatin-1 and stress responses because the central nesfatin-1 system is stimulated by stress and activates CRH, NA, and 5-HT neurons as well as the HPA axis, thereby evoking both central and peripheral stress responses (40,41). According to the literature, nesfatin-1 has homeostatic, anti-ischemic, anti-inflammatory, and anti-apoptotic properties (13,16,17). Thus, we aimed to investigate the effect of nesfatin-1 on the plasma level of cortisol in a rat model of intestinal I/R-based stress.…”

“…Nesfatin produces three major peptide products such as nesfatin-1 (spanning residues 1-82), nesfatin-2 (residues 85-163), and named it NUCB2-encoded satiety and the fat-influencing protein as nesfatin (15). Nesfatin-1 is involved in the regulation of homeostasis and has anti-inflammatory, anti-apoptotic, and anti-ischemic properties (13,16,17).…”