Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats / Efeito do Pós-Condicionamento Isquêmico na Hemodinâmica e nos Níveis Cardíacos de Óxido Nítrico em Ratos com Hipotireoidismo

Background: Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. Objective: The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Methods: Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Results: Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NOx) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NOx concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Conclusion: Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group. .

Fundamento: O pós-condicionamento isquêmico (PCI) é um método potente utilizado para proteger o coração contra a lesão de isquemia-reperfusão (I/R). Não está claro se o PCI é eficaz quando a doença cardíaca isquêmica é acompanhada de comorbidades, tais como hipotireoidismo. Objetivo: O objetivo deste estudo foi determinar o efeito do PCI sobre a lesão de I/R do miocárdio em ratos machos com hipotireoidismo. Métodos: O hipotireoidismo foi induzido pela administração de propiltiouracila em água potável na concentração de 500 mg/L durante 21 dias. Os corações de ratos controle e com hipotireoidismo foram perfundidos utilizando o aparelho de Langendorff e expostos a isquemia global por 30 minutos, seguido de reperfusão por 120 minutos. O PCI foi iniciado imediatamente após a isquemia. Resultados: O hipotireoidismo e PCI aumentaram significativamente a pressão ventricular esquerda desenvolvida (PVED) e as taxas máximas de variação positiva (+dp/dt) e negativa (–dp/dt) da pressão ventricular esquerda durante a reperfusão em ratos controle (p < 0,05). No entanto, o PCI não teve efeito aditivo no restabelecimento da PVED e das ±dp/dt em ratos com hipotireoidismo. Além disso, o hipotireoidismo diminuiu significativamente os níveis basais séricos (72,5 ± 4,2 vs. 102,8 ± 3,7 μmol/L; p < 0,05) e cardíacos (7,9 ± 1,6 vs. 18,8 ± 3,2 μmol/L; p < 0,05) de NOx. Os níveis cardíacos de NOx não se alteraram no grupo com hipotireoidismo após I/R e PCI mas foram significativamente maiores e menores (p < 0,05) nos grupos controle após I/R e PCI, respectivamente. Conclusão: O hipotireoidismo protegeu o coração da lesão de I/R, o que pode ser devido à diminuição dos níveis séricos e cardíacos basais de óxido nítrico (NO) e à diminuição dos níveis de NO após I/R. No entanto, o PCI não diminuiu os níveis de NO e não conferiu proteção adicional ao grupo com hipotireoidismo. .

Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes

The worldwide prevalence of obesity is steadily increasing, nearly doubling between 1980 and 2008. Obesity is often associated with insulin resistance, a major risk factor for type 2 diabetes mellitus (T2DM): a costly chronic disease and serious public health problem. The underlying cause of T2DM is a failure of the beta cells of the pancreas to continue to produce enough insulin to counteract insulin resistance. Most current T2DM therapeutics do not prevent continued loss of insulin secretion capacity, and those that do have the potential to preserve beta cell mass and function are not effective in all patients. Therefore, developing new methods for preventing and treating obesity and T2DM is very timely and of great significance. There is now considerable literature demonstrating a link between inhibitory guanine nucleotide-binding protein (G protein) and G protein-coupled receptor (GPCR) signaling in insulin-responsive tissues and the pathogenesis of obesity and T2DM. These studies are suggesting new and emerging therapeutic targets for these conditions. In this review, we will discuss inhibitory G proteins and GPCRs that have primary actions in the beta cell and other peripheral sites as therapeutic targets for obesity and T2DM, improving satiety, insulin resistance and/or beta cell biology.

Gene expression profiling of light-induced retinal degeneration in phototransduction gene knockout mice

Exposure to light can induce photoreceptor cell death and exacerbate retinal degeneration. In this study, mice with genetic knockout of several genes, including rhodopsin kinase (Rhok-/-), arrestin (Sag-/-), transducin (Gnat1-/-), c-Fos (c-Fos-/-) and arrestin/transducin (Sag-/-/Gnat1-/-), were examined. We measured the expression levels of thousands of genes in order to investigate their roles in phototransduction signaling in light-induced retinal degeneration using DNA microarray technology and then further explored the gene network using pathway analysis tools. Several cascades of gene components were induced or inhibited as a result of corresponding gene knockout under specific light conditions. Transducin deletion blocked the apoptotic signaling induced by exposure to low light conditions, and it did not require c-Fos/AP-1. Deletion of c-Fos blocked the apoptotic signaling induced by exposure to high intensity light. In the present study, we identified many gene transcripts that are essential for the initiation of light-induced rod degeneration and proposed several important networks that are involved in pro- and anti-apoptotic signaling. We also demonstrated the different cascades of gene components that participate in apoptotic signaling under specific light conditions.