Ghrelin as a treatment for cardiovascular diseases.

G hrelin, a growth hormone–releasing peptide that was first discovered in the stomach of rats in 1999, is an endogenous ligand of growth hormone secretagogue receptors (GHSRs). 1 Through binding to its receptors in the brain, ghrelin was initially shown to strongly stimulate the release of growth hormone and promote food intake. 2 Subsequent studies revealed that GHSRs are expressed ubiquitously in many organs and tissues, and ghrelin functionally participates in the regulation of diverse processes including appetite con-The primary receptor of ghrelin is currently thought to be GHSR1a; however, other unidentified receptors might exist. The high expression of GHSR1a in the heart and large vessels provides evidence of its cardiac activity , 7 indicating ghrelin is a promising new therapeutic agent for cardiovascular diseases. In this review, we discuss some of the characteristic features of ghrelin treatment and its possible therapeutic roles in animals and patients afflicted with common cardiovascular diseases. Ghrelin is produced predominantly in the stomach and is secreted from the submucosal layer into the bloodstream but not into the gastrointestinal tract. In situ analyses revealed that ghrelin and its mRNA are mainly localized in X/A-like cells, a major endocrine population in the gastric oxyntic mucosa that are morphologically similar to pancreatic α cells. 1 Cells that produce low levels of ghrelin are also found in the lung, Ghrelin is reportedly produced in neoplastic tissues such as gastric and intestinal carcinoids and medullary thyroid carcinomas. 19–21 In addition to endogenous ghrelin, growth hormone secretagogues, a heterogeneous group of synthetically produced peptides and non-peptides, have been developed as ghrelin alternatives that can bind GHSRs and stimulate growth hormone secretion in both animals and human subjects. The predominant active form of human ghrelin is a 28-aa peptide that is octanoylated at the serine-3 position by n-octa-noic acid. This acylation of ghrelin is essential for it to bind to GHSR1a, which in turn is required for its growth hormone– releasing activity and most likely for its other endocrine actions as well. 22–25 However, nonacylated ghrelin is present in human serum in far greater quantities than acylated ghrelin. In healthy adults, the plasma concentration of acylated ghrelin is 10 to 20 fmol/mL, whereas total ghrelin is 100 to 150 fmol/ mL. 26 Although nonacylated ghrelin does not bind to and activate GHSR1a and thus seems to be devoid of any endocrine activity, some studies reported that it exerts some nonendo-crine activity …