| Description |
Chromogrania A (Chga), 48-kDa acidic secretory pro-protein, is ubiquitously expressed in neuroendocrine tissues, and proteolytically processed into several biologically active peptides, including the dysglycemic pancreastatin (PST), vasorelaxant vasostatin, catecholamine release inhibitory and antihypertensive catestatin (CST). Chga knockout (KO) mice are hypertensive, hyperadrenergic and insulin sensitive compared to wild type control. Lack of PST increases insulin sensitivity and helps maintain euglycemia in KO mice by relieving inhibition from IRS1/2-PI 3 kinase-Akt signaling (achieved through suppression of cPKC and NOS activity) leading to increased suppression of hepatic gluconeogegesis. Since PST is overexpressed in T2DM, our observations may have implications for the pathogenesis and treatment of diabetes. Our data propose that loss of PST in KO mice protects against possible hypertension–induced metabolic disorders.
Ablation of Chga expression results in global disturbances in autonomic function (both para-sympathetic and sympathetic) and baroreceptor sensitivity, those can be rescued by replacement of CST. Dysregulated reactive oxygen species (ROS) production has the potential to hijack physiological excitatory pathways to elevate blood pressure. Our results thus point to a role for novel pathways in the genesis and consequences of hypertension, and suggest new strategies for approaching the pathogenesis and treatment of hypertension.
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