Upregulation of cardiovascular ghrelin receptor occurs in the hyperdynamic phase of sepsis

Abstract

Ghrelin, a newly identified endogenous ligand for growth hormone secretagogue receptor 1a (GHSR-1a, i.e., ghrelin receptor), was recently demonstrated to be a potent vasoactive peptide. Although sepsis is characterized by an early, hyperdynamic phase, it remains unknown whether ghrelin or GHSR-1a plays a role in the cardiovascular response to sepsis. To determine this, polymicrobial sepsis was induced by cecal ligation and puncture in male adult rats. At 5 h (i.e., early sepsis) or 20 h (i.e., late sepsis) after cecal ligation and puncture, blood and tissue samples were collected. Ghrelin levels and ghrelin and GHSR-1a mRNA expression were assessed by RIA and RT-PCR, respectively. In addition, GHSR-1a protein levels in aorta, heart, and small intestine were determined by Western blotting. The vascular response to ghrelin was determined by using an isolated gut preparation. A primary rat aortic smooth muscle cell culture was used to determine the effects of LPS on GHSR-1a expression. The results indicate that although ghrelin levels decreased at early and late sepsis, its receptor was markedly elevated in early sepsis. Moreover, ghrelin-induced relaxation in resistance blood vessels of the isolated small intestine increased significantly during early sepsis but was not altered in late sepsis. Furthermore, GHSR-1a expression in smooth muscle cells was significantly increased at mRNA and protein levels with stimulation by LPS at 10 ng/ml. These results demonstrate that GHSR-1a expression is upregulated and vascular sensitivity to ghrelin stimulation is increased in the hyperdynamic phase of sepsis.

Human Ghrelin Ameliorates Organ Injury and Improves Survival after Radiation Injury Combined with Severe Sepsis

“…Similar to CLP alone animals (19), serum levels of ghrelin in RCI animals decreased to 87 ± 20 pg/mL (P < 0.05), representing a 35% reduction at 20 h after RCI (68 h after irradiation or 20 h after CLP). And ghrelin gene expression in the stomach (the major source of ghrelin in the circulation [11]) was decreased by 87% at 20 h after RCI (P < 0.05, Figure 1B).…”

“…It has been linked to the regulation of pituitary hormone secretion, feeding, energy homeostasis, gastrointestinal function, cardiovascular system, and immune system (16)(17)(18). Our recent studies have shown that circulating levels of ghrelin decreased significantly in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), and ghrelin administration decreases inflammatory responses, improves organ blood flow, attenuates tissue injury, and reduces mortality under such conditions (18)(19)(20)(21). However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure.…”

Characterization of a far-red analog of ghrelin for imaging GHS-R in P19-derived cardiomyocytes

“…GHS-R expression is up-regulated in left ventricular tissue from patients with congestive heart failure [3] and atherosclerosis [8], as well as in the hearts of rats during the hyperdynamic phase of sepsis [28]. These results indicate that GHS-R signaling is altered in cardiovascular disease, and point toward the use of ghrelin in pharmacologic therapy of heart disease.…”

The role of ghrelin in energy homeostasis and its potential clinical relevance (Review)

“…In rodents, ghrelin attenuated endotoxin-induced anorexia, reduced cytokine production, and improved mortality associated with lipopolysaccharide (LPS)-induced endotoxic shock (43)(44)(45). In a well-designed series of studies, Dixit et al showed that ghrelin and the GHS-R are found in human T cells and monocytes, where ghrelin specifically inhibited the chronic synthesis of pro-inflammatory anorectic cytokines such as leptin, interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor · (46).…”