Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.

Continuous renal replacement therapy for haemodynamic collapse and rhabdomyolysis induced by pheochromocytoma crisis.

Pheochromocytoma associated with pregnancy is not common. Caesarean section may induce pheochromocytoma crisis, resulting in a lethal condition. The clinical picture of pheochromocytoma crisis is extremely variable. In this report, we describe a case of severe pheochromocytoma crisis induced by caesarean section presenting with hyperpyrexia, haemodynamic collapse, muscle weakness, heart failure, and acute kidney injury. Furthermore, we report that the muscle weakness was a manifestation of rhabdomyolysis, resulting from the pheochromocytoma crisis. Standard medical therapy failed to halt the patient's rapidly deteriorating condition. Continuous renal replacement therapy removed catecholamines from the circulation, resulting in improvement of haemodynamics and abrogation of rhabdomyolysis.

[Effects of endothelial progenitor cells and endothelial outgrowth cells in repair of injured carotid vessel: a comparative study with rabbits].

OBJECTIVE: To compare the effects of endothelial progenitor cells (EPCs) and endothelial outgrowth cells (EOCs) on the repair of injured vessels. METHODS: Mononuclear cells (MNCs) were isolated from rabbit peripheral blood by density-gradient centrifugation. EPCs and EOCs were obtained from the culture of MNCs and labeled with the cell dye CM-DiI for cells tracking. Eighteen rabbits were made into models of balloon-injured common carotid artery and then divided into 2 equal groups to undergo injection of the suspensions of EPCs or EOCs. Nine rabbits underwent injection of normal saline as control group. Four weeks after transplantation, the rabbits underwent venous injection of Evans blue, and then were killed with the injured vessels taken out. Fluorescence-labeled both types of cells, endothelial regeneration rate and IA/MA ratio were detected. RESULTS: Four weeks after transplantation, fluorescence-labeled EPCs and EOCs were detected within the tunica intima, mostly in the neointima and on the luminal surface of injured vessel. The endothelialization area of denuded vessel of the EPC and EOC groups were 91.6% +/- 3.6% and 89.1% +/- 6.3% respectively, both significantly larger than that of the control group (62.1% +/- 7.5%, both P < 0.01), however, without significant difference between the 2 former groups (P = 0.50). The intima area/media area ratio of the EPC and EOC groups were 0.48 +/- 0.11 and 0.44 +/- 0.06, both significantly lower than that of the control group (0.88 +/- 0.14, both P < 0.01), however, without significant difference between the 2 former groups (P = 0.59). CONCLUSION: Transplantation of both EPCs and EPCs accelerate the reendothelialization and reduce the neointimal formation with similar effects.