Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury

BACKGROUND: Recent studies show that erythropoietin (EPO) plays a protective role in brain ischemia. In this condition, administration of EPO protects neurons from ischemic damage. Recently, it has been shown that in patients with chronic heart failure (CHF), EPO treatment improved cardiac function. In the present study we assessed the role of EPO and EPO-receptor (EPO-R) in the heart. METHODS AND RESULTS: We studied the presence and functionality of the EPO-R in isolated rat hearts in the Langendorff set-up. Hearts were perfused for 20 min with 10 U/ml EPO or vehicle. Immunohistochemistry revealed the presence of the EPO-R on endothelial cells, fibroblasts and to a lesser extent cardiomyocytes. Furthermore, perfusion with EPO resulted in a 50% increase in the phosphorylated MAP kinases p42/p44. To evaluate the protective role of EPO in cardiac ischemia, we performed low-flow (0.6 ml/min) ischemia/reperfusion experiments in isolated rat hearts. Administration of EPO (10 U/ml) reduced the cellular damage by 56% (P<0.05) during reperfusion, diminished apoptosis by 15% (P<0.05) and resulted in a significantly improved recovery of left ventricular pressure (P=0.02) and coronary flow (P=0.01). CONCLUSION: The present data suggest that a functional EPO-R is present in rat adult cardiac tissue and that exogenous EPO administration improves cardiac function after ischemia/reperfusion injury.     

Why detailed model gene studies in higher eukaryotes are still necessary

Alterations in gene expression programmes are controlled by sequence‐specific DNA‐binding proteins that interact with the epigenetic regulatory machinery. The sum of such processes comprises a gene regulatory network and differentiation processes involve transitions between such networks. However, while great progress has been made to identify network components, this list is not complete, and we still do not fully understand how they work together. In this article, I argue that one reason for this lack of knowledge is the fact that we still do not understand what controls the cell stage and cell state‐specific regulation of individual genes and review examples highlighting this notion.     

Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter

Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP⁺). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP⁺ uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP⁺ uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC₅₀?=?44?±?2 μM). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 μM ASP⁺, which demonstrated competitive or mixed type of interaction (K _i?=?93 ± 16 μM). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP⁺ uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia.     

Expectancies, Socioeconomic Status, and Self-Rated Health: Use of the Simplified TOMCATS Questionnaire

Background

Coping has traditionally been measured with inventories containing many items meant to identify specific coping strategies. An alternative is to develop a shorter inventory that focusses on coping expectancies which may determine the extent to which an individual attempts to cope actively.

Purpose

This paper explores the usefulness and validity of a simplified seven-item questionnaire (Theoretically Originated Measure of the Cognitive Activation Theory of Stress, TOMCATS) for response outcome expectancies defined either as positive (“coping”), negative (“hopelessness”), or none (“helplessness”). The definitions are based on the Cognitive Activation Theory of Stress (CATS; Ursin and Eriksen, Psychoneuroendocrinology, 29(5):567–92, 2004). The questionnaire was tested in two different samples. First, the questionnaire was compared with a traditional test of coping and then tested for validity in relation to socioeconomic differences in self-reported health.

Methods

The first study was a comparison of the brief TOMCATS with a short version of the Utrecht Coping List (UCL; Eriksen et al., Scand J Psychol, 38(3):175–82, 1997). Both questionnaires were tested in a population of 1,704 Norwegian municipality workers. The second study was a cross-sectional analysis of TOMCATS, subjective and objective socioeconomic status, and health in a representative sample of the Swedish working population in 2003–2005 (N?=?11,441).

Results

In the first study, the coping item in the TOMCATS questionnaire showed an expected significant positive correlation with the UCL factors of instrumental mastery-oriented coping and negative correlations with passive and depressive scores. There were also the expected correlations for the helplessness and hopelessness scores, but there was no clear distinction between helplessness and hopelessness in the way they correlated with the UCL. In the second study, the coping item in TOMCATS and the three-item helplessness scores showed clear and monotonous gradients over a subjective socioeconomic status (SES) ladder. Positive response outcome expectancy (“coping”) was related to high subjective SES and no expectancy (“helplessness”) to low subjective SES. In a model including age and sex, TOMCATS scores explained more variance (r ²?=?0.16) in self-reported health than both subjective (r ²?=?0.08) and objective SES (r ²?=?0.02).

Conclusion

The brief TOMCATS questionnaire showed acceptable and significant correlations with a traditional coping questionnaire and is sensitive enough to register systematic differences in response outcome expectancies across the socioeconomic ladder. The results furthermore confirm that psychological and learning factors contribute to the socioeconomic gradient in health.     

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65×10⁻⁵) and diastolic BP (P=7.61×10⁻³) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0×10⁻³). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.