Antibacterial and Antifungal Activities of Vasostatin-1, the N-terminal Fragment of Chromogranin A

Abstract

Vasostatin-1, the natural N-terminal 1-76 chromogranin A (CGA)-derived fragment in bovine sequence, has been purified from chromaffin secretory granules and identified by sequencing and matrix-assisted laser desorption time-of-flight mass spectrometry. This peptide, which displays antibacterial activity against Gram-positive bacteria at micromolar concentrations, is also able to kill a large variety of filamentous fungi and yeast cells in the 1-10 M range. We have found that the C-terminal moiety of vasostatin-1 is essential for the antifungal activity, and shorter active peptides have been synthesized. In addition, from the comparison with the activity displayed by related peptides (human recombinant and rat synthetic fragments), we could determine that antibacterial and antifungal activities have different structural requirements. To assess for such activities in vivo, CGA and CGA-derived fragments were identified in secretory material released from human polymorphonuclear neutrophils upon stimulation. Vasostatin-1, which is stored in a large variety of cells (endocrine, neuroendocrine, and neurons) and which is liberated from stimulated chromaffin and immune cells upon stress, may represent a new component active in innate immunity.

Effects of Acute Prolonged Strenuous Exercise on the Salivary Stress Markers and Inflammatory Cytokines

“…CgA exists in various endocrine organs and its secretion is regulated by the SAM system 15,16) . In vitro experiments have also demonstrated that CgA exhibits antifungal and antibacterial properties 17,18) . Salivary CgA concentration increases rapidly under psychosomatic stress 19) , although the response of CgA to exercise is yet to be determined.…”

Cleavage of Chromogranin A N-terminal Domain by Plasmin Provides a New Mechanism for Regulating Cell Adhesion

“…Previous studies showed that a peptide encompassing residues 47-66, called chromofungin, could interact with lipids and penetrate into the cytoplasm of fungi (27,28). In addition, it has been shown that chromofungin can inhibit calcineurin, a calmodulin-activated phosphatase (28).…”

“…Thus, chromaffin cells possess in their microenvironment all of the components necessary for exerting a tightly regulated proteolytic cleavage of CgA. Plasminogen activation and CgA processing may not be limited to the surface of chromaffin cells, because many other neuroendocrine and non-neuroendocrine cells can express these molecules (3,27). Given the well recognized importance of fibroblasts and plasminogen activation in tissue invasion, remodeling, and repair (49 -52), the interplay between CgA and the plasminogen/plasmin system could provide a novel mechanism for regulating fibroblast adhesion and function in physiopathological conditions characterized by CgA hyperproduction, such as neuroendocrine tumors and chronic heart failure.…”

“…These fragments suppress vasoconstriction in isolated blood vessels (22)(23)(24). Vasostatin-1 can also inhibit parathyroid hormone secretion (25), is neurotoxic in neuronal/microglial cell cultures (26), and induces antibacterial and anti-fungal effects (27). The structural determinants of these activities are located in different regions of the N-terminal domain.…”

“…The structural determinants of these activities are located in different regions of the N-terminal domain. For example, peptide 1-40, containing the Cys 17 -Cys 38 disulfide bridge, induces vasodilator effects and inhibition of parathormone secretion, whereas peptide 47-60 can kill a variety of filamentous fungi (27,28).…”