Chromogranin A: a novel susceptibility gene for essential hypertension

Abstract

Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues. Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive peptides such as vasostatin-I (human CHGA(1-76)) and catestatin (human CHGA(352-372)) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover, genetic variants in the promoter, catestatin, and 3'-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes CHGA as a novel susceptibility gene for EH.

Fig. 1

Schematic organization of the human CHGA gene and its protein product. Top panel The human CHGA gene spanning 12,194 bp in chromosome 14 (from base position 92459198 to 92471391) consists of 8 exons separated by seven introns (UCSC Genome Browser refGene NM_001275). UTR Untranslated region, Ex exon, Int intron. Bottom panel The translated protein product consists of 457 amino acids, of which the first 18 residues serve as the signal peptide (SP). The mature protein undergoes proteolytic cleavage to generate several bioactive peptides. Localizations of the vasoactive peptide vasostatin-I (1–76 amino acids; VST) and catecholamine release inhibitory peptide catestatin (352–372 amino acids; CST) are indicated. The schemes are not drawn to scale

Fig. 2

Plausible molecular mechanisms of action of the CHGA-derived peptides vasostatin-I and catestatin in various cell types. A schematic of the major signaling pathways by which these peptides may exert their cardiovascular activities is presented. Catestatin acts on (1) mast cells to stimulate release of the vasodilator histamine in a receptor-independent manner via inhibitory heterotrimeric G-proteins [41], (2) chromaffin cells/neurons to inhibit exocytotic release (that involves intracellular free Ca²⁺-triggered docking of catecholamine storage vesicles on the cytoplasmic membrane) of catecholamines via non-competitive blocking of nAChR [29], (3) endocardial endothelial cells to activate release of the vasorelaxant NO via Protein kinase B signaling to eNOS [95]. Vasostatin-I acts on (1) endothelial endocardial cells to modulate NO release via the PTX-sensitive G_i/0-Akt-eNOS signaling similar to catestatin [82] and (2) endothelial cells to inhibit endothelial dysfunction via down-regulation of p38 MAP kinase phosphorylation involving protection of G_iα subunit of G_i proteins, which tonically inhibit downstream signaling through Hsp 27 and the contractile apparatus [41]. ER Endoplasmic reticulum, GC Golgi complex, NM nuclear membrane, CM cytoplasmic membrane, CHGA chormogranin A, Ach Acetylcholine, nAChR nicotinic acetyl choline receptor, NO nitric oxide, Akt Protein kinase B, eNOS endothelial nitric oxide synthase, PI-3K phosphoinositide 3-kinase, MAPK mitogen activated protein kinase, HSP heat shock protein

Fig. 3

Catestatin infusion results in lowering of blood pressure in mice. Systolic blood pressure (SBP) was measured before and 120 min after injection of catestatin (20 nmol/25 g body weight, intraperitoneally; expected to result in a concentration of ~4 μM in the extracellular space) to four chga knock out (chga ^−/−) and four wild-type littermate (chga ^+/+) by telemetry (chga ^−/−). The data for generating this plot were taken from [25]. The data were evaluated by unpaired Student’s t test with the InStat 3 program (GraphPad Software). An exaggerated lowering of SBP was observed in the case of chga ^−/− mice displaying anti-hypertensive effect of the peptide