Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • BIIE 0246 Recently results obtained by our group

    2022-01-21

    Recently, results obtained by our group have demonstrated that hEECs are able to secrete NPY into the extracellular medium and that this peptide can induce an increase in the [Ca]i of these cells (Jacques et al., 2003b). In light of these results and those obtained in this study, we can speculate that the released NPY can then act in a paracrine fashion on the subjacent cardiomyocytes, or in an autocrine fashion on hEECs themselves to maintain its own secretion and/or induce the release of other peptides such as ET-1 (Abdel-Samad et al., 2012, Jacques and Abdel-Samad, 2007). The luminal secretion by EECs of both these peptides into the ventricular cavity may affect their arterial circulating levels, whereas their abluminal secretion into the subendocardial space or the extracellular matrix located between hEECs and the underlying myocardium would certainly contribute to normal functioning of the heart (Abdel-Samad et al., 2007, 2012). Furthermore, overstimulation of NPY or ET-1 secretion by hEECs may lead or contribute to abnormal heart function such as arrhythmia, hypertrophy and heart failure (Jacques and Abdel-Samad, 2007, Abdel-Samad et al., 2007). In fact, the correlation between elevated plasma levels of NPY and ET-1 on one hand and cardiac and vascular pathophysiological states on the other hand has been documented in the literature. Increased NPY concentrations were reported in cases of hypertension and high plasma NPY immunoreactivity was detected in patients with acute myocardial ischemia (Ullman et al., 1994a) and congestive heart failure (Ullman et al., 1994b). The EEC secreted blood borne NPY and ET-1 could be the result of a cross talk between the sympathetic nerves controlled by the central nervous system and EECs (Marron et al., 1994). The secreted blood borne NPY and ET-1 would contribute to cardiovascular function in health and disease directly or indirectly via their crosstalk with circumventricular organs modulating the activity of the BIIE 0246 cardiovascular centers (Ufnal and Skrzypecki, 2014). Therefore, released hormones by EECs at the exit of the heart as well as the tuning of the level of these hormones at the entrance of the arterial circulation would contribute, along with the nervous system, to not only the excitation-secretion coupling of EECs and the excitation-contraction coupling of cardiomyocytes (Abdel-Samad et al., 2012, Brutsaert and Andries, 1992, Shah et al., 1996, Jacques et al., 2003a, Jacques et al., 2003b), but also the physiological and pathophysiological states of both heart and vascular systems. Our published results also show that the Y2 and the Y5, but not the Y1, receptors mediate NPY-induced excitation-secretion coupling in EECs (Abdel-Samad et al., 2012). Thus, it is highly important to consider controlling ET-1 circulating level via blockade of Y2 and/or Y5 receptor activation (Abdel-Samad et al., 2012). In addition, since the ET-1 released by NPY is contributing further to its own release via activation of the ETA and ETB receptors, then it is highly possible to control, at least in part, the actions of NPY-induced increase of ET-1 secretion via blockade of ETA or ETB receptors. Furthermore, such a blockade of ET-1 secretion induced by NPY would control only the secretory capacity of REECs since NPY-induced ET-1 secretion in LEECs is insensitive to ETA or ETB blockade. In addition, since secretion of REECs takes place at the entry of the pulmonary circulation, thus, blockade of ETA or ETB receptor activation at that level would preferentially affect the level of tuning of ET-1 by LEECs. It has become increasingly apparent from data in the literature that receptor activation can result in much more complex patterns of signaling within cells than previously thought. There is considerable evidence, for example, that signaling through GPCRs that couple preferentially to a certain signaling pathway can be modulated by inputs from GPCRs that couple to other pathways. Such crosstalk between receptors can result in loss of function at times, and gain or enhancement of function at others (Werry et al., 2003). The crosstalk between NPY receptors, which are mainly Gi/o coupled receptors, and other GPCRs such as α1-adrenoceptors, which are Gq/11coupled, and β-adrenoceptors has been reported in vascular smooth muscle cells (Racchi et al., 1999, Pons et al., 2003) and may also be true of other cell types. Such synergistic crosstalk results in the augmentation of physiological responses such as smooth muscle contraction (in the case of interaction between the NPY receptors and α1-adrenoceptors) and mitogenesis (in the case of interaction between the NPY receptors and β-adrenoceptors) (Selbie and Hill, 1998, Pons et al., 2003). Based on our previous (Abdel-Samad et al., 2012) and present results, a similar synergistic crosstalk could be taking place between the NPY receptors, Y2 and Y5, which are, as mentioned before, mainly Gi/o coupled receptors, and the ET-1 receptors, ETA and ETB, which couple, among others, to Gq/11 proteins. This should be definitely further explored in the future because it could have important implications on the physiological and pathophysiological consequences of receptor activation, and thus, could provide novel targets for therapeutic interventions (Werry et al., 2003).