Background: The hyaluronan receptor CD44 interacts with the PDGF β-receptor and the TGFβ type I receptor. Results: CD44, PDGF β-receptor and TGFβ type I receptor affect each other's signaling, stability and function. Conclusion: Cross-talk between PDGF β-receptor and TGFβ type I receptor occurs in human dermal fibroblasts. Significance: This study reveals novel modulatory mechanisms of PDGF and TGFβ signaling. Growth factors, such as platelet-derived growth factor BB (PDGF-BB) and transforming growth factor β (TGFβ), are key regulators of cellular functions, including proliferation, migration, and differentiation. Growth factor signaling is modulated by context-dependent cross-talk between different signaling pathways. We demonstrate in this study that PDGF-BB induces phosphorylation of Smad2, a downstream mediator of the canonical TGFβ pathway, in primary dermal fibroblasts. The PDGF-BB-mediated Smad2 phosphorylation was dependent on the kinase activities of both TGFβ type I receptor (TβRI) and PDGF β-receptor (PDGFRβ), and it was prevented by inhibitory antibodies against TGFβ. Inhibition of the activity of the TβRI kinase greatly reduced the PDGF-BB-dependent migration in dermal fibroblasts. Moreover, we demonstrate that the receptors for PDGF-BB and TGFβ interact physically in primary dermal fibroblasts and that stimulation with PDGF-BB induces internalization not only of PDGFRβ but also of TβRI. In addition, silencing of PDGFRβ by siRNA decreased the stability of TβRI and delayed TGFβ-induced signaling. We further show that the hyaluronan receptor CD44 interacts with both PDGFRβ and TβRI. Depletion of CD44 by siRNA increased signaling via PDGFRβ and TβRI by stabilizing the receptor proteins. Our data suggest that cross-talk between PDGFRβ and TβRI occurs in dermal fibroblasts and that CD44 negatively modulates signaling via these receptors.

G-protein-coupled receptors (GPCRs) are the most abundant receptors in the heart and therefore are common targets for cardiovascular therapeutics. The activated GPCRs transduce their signals via heterotrimeric G-proteins. The four major families of G-proteins identified so far are specified through their α-subunit: Gαi, Gαs, Gαq and G12/13. Gαi-proteins have been reported to protect hearts from ischemia reperfusion injury. However, determining the individual impact of Gαi2 or Gαi3 on myocardial ischemia injury has not been clarified yet. Here, we first investigated expression of Gαi2 and Gαi3 on transcriptional level by quantitative PCR and on protein level by immunoblot analysis as well as by immunofluorescence in cardiac tissues of wild-type, Gαi2-, and Gαi3-deficient mice. Gαi2 was expressed at higher levels than Gαi3 in murine hearts, and irrespective of the isoform being knocked out we observed an up regulation of the remaining Gαi-protein. Myocardial ischemia promptly regulated cardiac mRNA and with a slight delay protein levels of both Gαi2 and Gαi3, indicating important roles for both Gαi isoforms. Furthermore, ischemia reperfusion injury in Gαi2- and Gαi3-deficient mice exhibited opposite outcomes. Whereas the absence of Gαi2 significantly increased the infarct size in the heart, the absence of Gαi3 or the concomitant upregulation of Gαi2 dramatically reduced cardiac infarction. In conclusion, we demonstrate for the first time that the genetic ablation of Gαi proteins has protective or deleterious effects on cardiac ischemia reperfusion injury depending on the isoform being absent.

Background: For the assessment of the left ventricular function and infarct size in acute myocardial infarction, brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) are useful for the prediction of a prognosis. The aim of the present study was to correlate left ventricular function and infarct size to the level of cTnI and BNP in acute myocardial infarction. Patients and Methods: We studied 40 patients (pts), with the first ST-segment elevation myocardial infarction (STEMI). We measured the level of BNP and cTnI on a single occasion at 96 hours after the onset of symptoms, and then compared it with echocardiography estimated systolic and diastolic ventricular function and infarct size — which was determined with numbers of ECG leads and classification into small and large infarct size (small infarct size 3-4 leads, large infarct size 6-9 leads). Results: Distribution of data was estimated by using the Shapiro-Wilk test. The data do not have normal distribution, so they are representative as a median and range. We used non-parametric statistic tests (Mann-Whitney tests) to compare and improve differences among the groups. For statistical correlation, we used the Sperman rank correlation. Data were analyzed using statistical program Arcus Quick Stat. There was significant inverse correlation between the level of BNP and EF (r = -0.504, P = 0.0016) and between BNP i E/A (r = -0.290, P = 0.00705). There was a strong inverse correlation between BNP and LV-EF in STEMI, such as between BNP and E/A, against cTnI no significant correlation with LV-EF and E/A in STEMI was found. There is no significant statistical difference between BNP and cTnI in small and large infarct size. Conclusion: A single BNP value at 96 hours after the onset symptoms of myocardial infarction proved useful for the estimation of LV systolic and diastolic function. In a direct comparison BNP disclosed a better performance for the estimation of LV-EF and E/A against cTnI. cTnI is useful for diagnosing early myocardial damage in acute myocardial infarction, suggesting an implementation of dual marker strategy in acute myocardial infarction for diagnostic and prognostic work-up.

E-mail: meldi@bih.net.ba Heart rate variability, a phenomenon of variations of the length of consecutive heat cycles reflects the autonomic modulation of the heart function. Parameters of monitoring the heart rate variability are suggested to be important in the assessment of autonomic neuropathy that may complicate several pathological conditions, with established clinical importance in predicting morbidity and mortality in patients with coronary syndrome and in patients with diabetes mellitus. The complexity of the critical illness of the subjects in the intensive care unit demands complex pharmacological and procedural therapeutic interventions and measures, which all have a significant impact on the parameters of heart rate variability. Such complex interactions limit the possibility to reach conclusions on a potential degree of the influences of the deteriorated organ function and the influence of the therapeutic interventions. Despite difficulties and limitations of interpretation of the variations and depression of the heart rate variability parameters, research in this field has been continuing. In this paper, different parameters of short-term heart rate variability monitored in 25 consecutive patients who were admitted to an adult intensive care medicine unit for different conditions of critical illness are presented.