Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca²⁺]_i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.     

New therapeutic approach for impaired arteriogenesis in diabetic mouse hindlimb ischemia.

BACKGROUND: The combined treatment of sustained-release basic fibroblast growth factor (Sr-bFGF) and a 5-hydroxytryptamine(2A) blocker, sarpogrelate, was evaluated to see whether it reversed the impaired collateral circulation in diabetic (DM) mouse hindlimb ischemia. METHOD AND RESULTS: Diabetic and normal mice with ischemic hindlimb were randomly assigned to 1 of 5 experimental groups (no treatment, sarpogrelate 50 mg . kg(-1) . day(-1), 20 microg or 50 microg Sr-bFGF and a combined treatment of 20 microg Sr-bFGF and sarpogrelate), and treated for 4 weeks. Tissue blood perfusion (TBP), vascular density (angiogenesis) and the number of mature vessels (arteriogenesis) were checked by the use of standard methods. Although angiogenesis was comparable (161+/-14 vs 154+/-12 vessels/mm(2)), the laser Doppler perfusion image index (LDPII) (0.43+/-0.11 (SD) vs 0.63+/-0.08, p<0.05) and arteriogenesis (8+/-3 vs 12+/-4 vessels/mm(2), p<0.05) were significantly lower in DM mice than those in normal mice. The dose of Sr-bFGF for the sufficient number of mature vessels (>or=45 vessels/mm(2)) and LDPII (>or=0.9) was 20 microg for the normal mice, and 50 microg for the DM mice, which was reduced with the aid of sarpogrelate. Conclusions A combined therapy of Sr-bFGF and sarpogrelate is effective for neovascularization to reverse the impaired arteriogenesis and TBP in DM mice.     

Clinical profile,management and outcome of pulmonary embolism in Shahid Gangalal National Heart Centre,Kathmandu, Nepal

Background and aims

Pulmonary embolism (PE) is associated with a significant mortality and morbidity. We aim to study clinical profile, management and outcome of PE at Shahid Gangalal National heart Centre, Kathmandu, Nepal.

AUF1 is upregulated by angiotensin II to destabilize cardiac Kv4.3 channel mRNA

Expression of cardiac myocyte Kv4 channels (Kv4.3 for human, Kv4.2 and Kv4.3 for rodents) is downregulated with hypertrophy in vivo leading to a decrease in the transient outward current (Ito). This effect is recapitulated in vitro with rat neonatal cardiac myocytes treated with angiotensin II (Ang II), which acts via AT₁ receptors, NADPH oxidase and p38 MAP kinase to destabilize the 3′ untranslated region (3′UTR) of the Kv4.3 channel messenger RNA (mRNA). Here deletion analysis and mutagenesis identify an AU-rich element (ARE) in the Kv4.3 3′UTR that is required for Ang II-induced destabilization. Overexpression of AUF1 (ARE/poly-(U)-binding/degradation factor 1), an RNA destabilizing protein, mimics and occludes the Ang II effect, while RNA interference targeted against AUF1 blocks the Ang II effect on the Kv4.3 3′UTR. Ang II upregulates AUF1 by activating AT₁ receptors, NADPH oxidase and p38 MAP kinase. Finally, pull-down assays establish that Ang II increases AUF1 binding to the ARE required for destabilization, while binding of the mRNA stabilizing protein HuR is unaffected. Hence, Ang II acts via AT₁ receptors, NADPH oxidase and p38 MAP kinase to upregulate AUF1, which in turn binds to an ARE in the Kv4.3 3′UTR to destabilize the channel mRNA.     

Chlamydia pneumoniae exposure and inflammatory markers in acute coronary syndrome (CIMACS)

Previous studies have shown higher levels of Chlamydia pneumoniae (C. pneumoniae, CP) antibody titers (CPIgG), C-reactive protein (CRP), and fibrinogen in patients with coronary artery disease. The role of these infectious and inflammatory markers in precipitating acute coronary syndrome (ACS) is unclear. We conducted a cross-sectional study on patients (n = 830, mean age 63 +/- 15 years, 57% male) admitted to the chest pain center of our institution. The differences in the CPIgG, CRP, and fibrinogen levels in patients who were diagnosed with ACS versus those who were not (non-ACS) were evaluated. CPIgG titers tended to be higher in the ACS group than in the non-ACS group. However, when different titers were used to define seropositivity, the difference achieved statistical significance only at the titer of > or =1:1,024 (35% vs 26%, p = 0.004). CRP (median 0.48 vs 0.33 mg/dl, p <0.0001), fibrinogen (median 317 vs 293 mg/dl, p <0.0001), and leukocyte count (median 7.7 vs 6.9 10(9)/L, p <0.0001) were higher in the ACS group. On multivariate analysis, CPIgG > or =1:1,024 (odds ratio [OR] 1.62), diabetes (OR 1.91), hypertension (OR 1.46), prior myocardial infarction (OR 1.78), smoking (OR 1.70), Caucasian race (OR 1.7), high-density lipoprotein (OR 0.98), and elevated troponin-T (OR 12.44) were the only factors independently associated with ACS. Thus, we found a strong association between high level seropositivity to CP and ACS. This may indicate recent re-infection or an exaggerated immune response to CP as an etiologic factor for ACS. This study also suggests that therapeutic interventions may need to be specifically targeted to these patients.     

Density and function of inward currents in right atrial cells from chronically fibrillating canine atria

OBJECTIVE: To determine whether I(Na) and I(CaL) are altered in function/density in right atrial (RA) cells from dogs with chronic atrial fibrillation (cAF dogs, episodes lasting at least 6 days) and whether the changes that occur differ from those in dogs with nonsustained or brief episodes of fibrillation (nAF dogs). METHODS: Using whole cell voltage clamp, sodium and calcium current density and function were determined in disaggregated RA cells from nAF, cAF and control atria (Con). Ca(2+) currents were studied with either Ca(2+) or Ba(2+) as charge carrier, as well as with either EGTA or BAPTA as the internal solution Ca(2+) chelator. RESULTS: After rapid atrial pacing, dogs can either fibrillate for short periods of time (nAF) or longer, more sustained periods (cAF). Both the Na(+) and Ca(2+) current decrease in cells of the nAF atria. Na(+) current density remains reduced in cAF cells with some slowing of recovery kinetics. Ca(2+) current density does not further decrease with persistent atrial fibrillation (cAF cells) remaining significantly different from Con cells. However, the difference in density of Ca(2+) currents between nAF and Con cells is negligible when Ba(2+) is charge carrier and when Ca(i) is quickly and effectively chelated with BAPTA. On the contrary, cAF I(BaL) densities remain significantly reduced compared to Con and nAF values when Ba(2+)/BAPTA conditions are used. CONCLUSIONS: Na(+) current density/function does not recover to Con values in cAF. Further these enhanced Ca(2+)-dependent inactivation processes contribute significantly to the reduction of I(CaL) density observed in nAF cells while reduction of Ca(2+) currents in cAF atria is probably by another mechanism