Intravenous clusterin administration reduces myocardial infarct size in rats
A. van DijkRob A. VermondPaul A.J. KrijnenLynda J.M. JuffermansNynke E. HahnSudesh P. MakkerLucien A. AardenErik HackMarieke SpreeuwenbergBert C. van RossumC. MeischlWalter J. PaulusFlorine J. van MilligenHans W.M. Niessen
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Eur J Clin Invest 2010; 40 (10): 893–902 Abstract Background Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. Methods Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. Results Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. Conclusions Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.Keywords:
Clusterin
The density of T3 nuclear receptors is known to vary with tissues and physiopathological conditions, but the factors involved in their regulation are still unknown. We have previously shown in the anterior pituitary gland that T3 modulates its own receptors; the density of T3 receptors in hypothyroid rats is half that in normal rats, and one injection of T3 is able to restore normal density of T3 receptors within 1-3 h. To determine whether T3 has a direct action on the synthesis of its nuclear receptor, the effect of cycloheximide (Cy) on T3-induced nuclear receptor was studied. In addition, the relationship between the density of pituitary T3 receptors and the secretion of TSH in different thyroid states was examined. In normal rats one injection of Cy (0.5-8 mg/100 mg BW) induced within 3 h a dose-dependent reduction in the density of pituitary T3 receptors as well as an important decrease in plasma TSH, with no changes in T4, T3, or pituitary TSH content. In hypothyroid rats the 50% decrease in the density of pituitary T3 receptors was not further reduced by 1 mg Cy. However, when the same dose of Cy was given 30 min before T3 it completely inhibited the induction by T3 of its receptors. When Cy was given 30 min or 1 h after T3 the inhibition was only partial. An inverse correlation was found between the density of T3 receptors in the pituitary gland and plasma TSH (r = -0.8128) in all experimental groups except those treated with Cy; this drug had an inhibitory effect on both TSH secretion and the density of receptors. The present data, therefore, support the view that T3 in the pituitary gland may induce the synthesis of its own nuclear receptors and that the density of T3 receptors is also involved in the control of TSH secretion.
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Brain natriuretic peptide
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The pituitary regulation of the sexually differentiated PRL receptor in rat liver was studied. PRL receptors were measured in a crude membrane fraction (105,000 × g pellet) using [125I]iodohuman PRL as tracer. Human GH (hGH), continuously administered by Alzet osmotic minipumps with an infusion rate of 5 μg/h for 1 week, was shown to induce PRL receptors in livers from male and female hypophysectomized-gonadectomized rats. The PRL receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and thyroidectomized male rats. In intact male rats given hGH, PRL receptors were increased to a female level in 4–7 days. hGH was effective in doses of 2.5 and 5 Μg/μl in inducing a female receptor pattern. The induced PRL receptors in male rats had characteristics similar to those of hepatic PRL receptors in female rats when data were calculated according to Scatchard (Kd = 0.13 × 10-9vs. 0.15 × 10-9 M; number of binding sites 88 vs. 57 fmol/mg protein). Also, the endogenous rat hormones, rat PRL (rPRL) and rat GH (rGH), were administered by minipumps to hypophysectomized male rats. With the infusion rate used (10 μg/h), rPRL had no effect, whereas rGH (NIAMDD-B6) increased PRL receptor levels to approximately 37% of the female control level. A more complete induction of PRL receptors (75% of the female control levels) in hypophysectomized males was achieved using another preparation of rGH (NIAMDD 1-4). Also, in hypophysectomized female rats, rPRL was ineffective in inducing PRL receptors. On the other hand, ovine PRL was found to give a partial restoration of PRL receptors in hypophysectomized female rats. The results indicate that GH or a peptide related to GH may be involved in the regulation of hepatic PRL receptors. However, the results do not rule out the possibility that rPRL, when present in doses other than those used in the present investigation, may also play a role in receptor regulation.
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The present study examined the role of clusterin in insulin resistance in high fat-fed wild-type and clusterin knockout (KO) mice. The plasma levels of glucose and C-peptide and islet size were increased in clusterin KO mice after an 8-week high-fat diet. In an ip glucose tolerance test, the area under the curve for glucose was not different, whereas the area under the curve for insulin was higher in clusterin KO mice. In a hyperinsulinemic-euglycemic clamp, the clamp insulin levels were higher in clusterin KO mice after the high-fat diet. After adjusting for the clamp insulin levels, the glucose infusion rate, suppression of hepatic glucose production, and glucose uptake were lower in clusterin KO mice in the high fat-fed group. The plasma levels of clusterin and clusterin mRNA levels in the skeletal muscle and liver were increased by the high-fat diet. The mRNA levels of the antioxidant enzymes were lower, and the mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 1 and cytokines and protein carbonylation were higher in the skeletal muscle and liver in clusterin KO mice after the high-fat diet. Palmitate-induced gene expressions of NOX1 and cytokines were higher in the primary cultured hepatocytes of clusterin KO mice compared with the wild-type mice. Clusterin inhibited the gene expression and reactive oxygen species generation by palmitate in the hepatocytes and C2C12. AKT phosphorylation by insulin was reduced in the hepatocytes of clusterin KO mice. These results suggest that clusterin plays a protective role against high-fat diet-induced insulin resistance through the suppression of oxidative stress and inflammation.
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The role of vasopressin (VP) in the regulation of pituitary corticotropin-releasing factor (CRF) receptors was studied by examining the effects of adrenalectomy and VP infusion on pituitary CRF receptors in genetically VP-deficient rats (di/di) and Long-Evans control rats. Binding studies with [125I]Tyr-ovine CRF in 30,000 × g anterior pituitary membranerich fractions revealed similar characteristics for the CRF receptors in Long-Evans and di/di rats, with Kd values of 2.4 ± 0.6 and 1.9 ± 0.2 nM, respectively, and receptor concentrations of 278 ± 31 and 286 ± 43 fmol/mg, respectively. Two days after adrenalectomy, the pituitary CRF receptor concentration decreased by 72 ± 4.2% in Long-Evans rats, but by only 20.3 ± 5.6% in di/di rats. CRF receptor affinity was unchanged after adrenalectomy (Kd = 1.7 ± 0.5 nM; n = 8). To determine whether VP deficiency is responsible for the smaller decrease in CRF receptor in di/di rats, the effect of exogenous VP infusion (100 ng/min) by sc osmotic minipumps was studied in adrenalectomized di/di rats. Two days after adrenalectomy, pituitary CRF receptors were reduced by 21 ± 8% in control di/di rats, whereas a 77.7 ± 1.8% decrease was observed in VP-infused di/di rats, comparable to the effect of adrenalectomy in Long-Evans rats. VP infusion also caused a significant 35 ± 2% decrease in CRF receptors in the pituitaries of sham-operated di/di rats, with no change in CRF receptor affinity. In Sprague-Dawley rats, VP or CRF infusion (100 ng/min) decreased pituitary CRF receptors by 14 ± 1.9% and 46 ± 3%, respectively. However, the combined infusion of both peptides caused a 65% ± 4.2 decrease, similar to that observed after adrenalectomy. In vitro incubation of quartered pituitaries with VP or CRF for 4 h reduced CRF receptors by 23.1 ± 8.2% and 38.2 ± 3.8%, respectively, while simultaneous preincubation with both peptides was followed by a decrease of 55.3 ± 5.3%. These findings indicate that increased hypothalamic release of VP contributes to the down-regulation of pituitary CRF receptors after adrenalectomy. (Endocrinology121: 2093–2098, 1987)
Corticotropin-releasing hormone
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Brain natriuretic peptide
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ABSTRACT A single injection of gonadotrophin-releasing hormone (GnRH) (60 ng s.c., 42·9 nmol) induced biphasic GnRH receptor regulation in normal intact adult female mice. A transient 22% receptor decrease occurred 30–60 min after injection of GnRH when peak serum decapeptide concentrations were reached (137 ± 41 ( s.e.m. ) ng/l). This GnRH receptor decrease occurred shortly after the peak serum LH values at 15–30 min. The subsequent rapid (within 1 h) return of GnRH receptor levels to normal suggested transient receptor occupancy by GnRH rather than true receptor loss. At 8 h after injection of GnRH a significant 35% increase in GnRH receptors was consistently observed, when serum GnRH levels were undetectable and serum LH had returned to basal levels. This receptor increase was not due to increased receptor affinity, and was prevented by a non-specific protein synthesis inhibitor. Ovariectomy, which caused a 50% fall in GnRH receptors (59·4 ± 4·9 fmol/pituitary gland in intact controls; 26·9 ± 2·6 in ovariectomized mice) abolished the induction by GnRH of its own receptors, although the initial transient decrease occurred over the period of the acute serum LH and FSH rise. Despite a 50% reduction in GnRH receptors in ovariectomized mice, increased serum gonadotrophin levels and responsiveness to GnRH were maintained, indicating dissociation between receptor changes and gonadotrophin levels. No GnRH receptor up-regulation was observed 8 h after a single GnRH injection (60 ng s.c.) in either intact or orchidectomized normal male mice. However, the same treatment doubled GnRH receptors in GnRH-deficient ( hpg ) female mice. While GnRH appears to up-regulate its own receptors by a direct action on pituitary gonadotrophs in the GnRH-deficient mouse its action in the normal female mouse pituitary appears secondary to stimulation of a gonadal product, presumably oestrogens. J. Endocr. (1985) 107, 41–47
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Corticosterone
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Left ventricular remodeling (LVR), an increase in left ventricular end-diastolic volume index > or = 20%, is an adverse consequence of myocardial infarction. The aim of this study was to assess the association between LVR and adiponectin, which has been shown to protect against myocardial ischemia-reperfusion injury.In 75 patients echocardiographic examination was performed one year after ST-segment elevation myocardial infarction, successfully treated with primary percutaneous coronary intervention (pPCI). Two groups of patients were analyzed: those with LVR (n = 15) and those without LVR (n = 60).The predictors of LVR were: anterior myocardial infarction, glucose at admission, baseline C-reactive protein, adiponectin, and echocardiographic parameters: left ventricular end-diastolic and end-systolic volume indices, ejection fraction < 40% and left ventricular wall motion score index (WMSI) at discharge. On multivariable regression analysis, lower adiponectin level (OR = 0.67, 95% CI 0.49-0.91, p < 0.05) and higher WMSI (OR = 20.14, 95% CI 2.62-154.82, p < 0.01) were the only independent negative predictors of LVR. The optimal cut-off for adiponectin for predicting LVR was < or = 4.7 mg/mL (sensitivity: 73%, specificity: 85%) and this level increased the risk of LVR 15-fold (95% CI 4.05-59.87, p = 0.0001).Baseline low blood adiponectin concentration, along with WMSI, can be considered as a predictor of the LVR in male patients one year after myocardial infarction and pPCI.
Ventricular remodeling
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