Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells.

Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted by hyperinsulinemia via an unknown mechanism. Thus, the goal of this study was to characterize the impact of hyperinsulinemia on the regulation of molecular targets involved in cerebral blood flow and insulin receptor internalization into brain endothelial cells. The phosphorylation of molecular targets associated with cerebral blood flow and insulin receptor internalization was assessed in hyperinsulinemic brain endothelial cells. Insulin receptor uptake into cells was also examined in the setting of endocytosis blockade. Our data demonstrate that hyperinsulinemia impairs the activation of endothelial nitric oxide synthase. These data correspond with an impairment in clathrin-mediated endocytosis of the insulin receptor and dysregulated phosphorylation of key internalization effectors. We conclude that hyperinsulinemia alters the phosphorylation of molecular targets involved in clathrin-mediated endocytosis, disrupts signaling through the insulin receptor, and hinders the capacity for blood flow regulation by brain endothelial cells.

Hyperinsulinemia alters insulin receptor presentation and internalization in brain microvascular endothelial cells.

Insulin receptors are internalized by endothelial cells to facilitate their physiological processes; however, the impact of hyperinsulinemia in brain endothelial cells is not known. Thus, the aim of this study was to elucidate the impact hyperinsulinemia plays on insulin receptor internalization through changes in phosphorylation, as well as the potential impact of protein tyrosine phosphatase 1B (PTP1B). Hippocampal microvessels were isolated from high-fat diet fed mice and assessed for insulin signaling activation, a process known to be involved with receptor internalization. Surface insulin receptors in brain microvascular endothelial cells were labelled to assess the role hyperinsulinemia plays on receptor internalization in response to stimulation, with and without the PTP1B antagonist, Claramine. Our results indicated that insulin receptor levels increased in tandem with decreased receptor signaling in the high-fat diet mouse microvessels. Insulin receptors of cells subjected to hyperinsulinemic treatment demonstrate splice variation towards decreased IR-A mRNA expression and demonstrate a higher membrane-localized proportion. This corresponded with decreased autophosphorylation at sites critical for receptor internalization and signaling. Claramine restored signaling and receptor internalization in cells treated with hyperinsulinemia. In conclusion, hyperinsulinemia impacts brain microvascular endothelial cell insulin receptor signaling and internalization, likely via alternative splicing and increased negative feedback from PTP1B.

Heart and Brain: Complex Relationships for Left Ventricular Dysfunction.

PURPOSE OF REVIEW: This review summarizes the evidence for the established vascular/hypoperfusion model and explores the new hypothesis that configures the heart/brain axis as an organ system where similar pathogenic mechanisms exploit physiological and pathological changes. RECENT FINDINGS: Although associated by common risk factors, similar epidemiological stratification and common triggers (including inflammation, oxidative stress, and hypoxia), heart failure and Alzheimer's disease have been, for long time, viewed as pathogenically separate illnesses. The silos began to be broken down with the awareness that vascular dysfunction, and loss of cardiac perfusion pump power, trigger biochemical changes, contributing to the typical hallmark of Alzheimer's disease (AD)-the accumulation of Aß plaques and hyperphosphorylated Tau tangles. Compromised blood flow to the brain becomes the paradigm for the "heart-to-head" connection. Compelling evidence of common genetic variants, biochemical characteristics, and the accumulation of Aß outside the brain suggests a common pathogenesis for heart failure (HF) and AD. These new findings represent just the beginning of the understanding the complex connection between AD and HF requiring further studies and interdisciplinary approaches. Altogether, the current evidence briefly summarized in this review, highlight a closer and complex relationship between heart failure and Alzheimer's that goes beyond the vascular/perfusion hypothesis. Genetic and biochemical evidence begin to suggest common pathogenic mechanisms between the two diseases involving a systemic defect in the folding of protein or a seeding at distance of the misfolded proteins from one organ to the other.