p27kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation

Abstract

p27kip1 (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

Mesenchymal stem cells attenuate doxorubicin‑induced cellular senescence through the VEGF/Notch/TGF‑β signaling pathway in H9c2 cardiomyocytes

“…The results of the present study suggested that MSCs exert an antisenescence effect by triggering the secretion of VEGF, and that this effect is reduced by an anti-VEGFR2 antibody. Asa previous study found that H9c2 cells also express VEGF (33), the present study used RT-qPCR analysis to examine the mRNA level of VEGF in the H9c2 cells, however the results of the RT-qPCR analysis showed no difference between the H9c2 cells cocultured with MScs and H9c2 cells alone. The increase of free VEGF in the H9c2 MSc coculture may result from the MScs only.…”

Naloxone attenuates ischemic brain injury in rats through suppressing the NIK/IKKα/NF-κB and neuronal apoptotic pathways

“…Our results suggest that IKKα is highly phosphorylated during cerebral ischemia-induced injury in pMCAO rats. IKK has been found to be activated in mouse/rat models of MCAO and myocardial infarction, although the associated mechanisms are obscure [1,30]. IKK phosphorylates NF-κB-bound IκBs and targets them for ubiquitin-dependent degradation, allowing the consequently liberated NF-κB dimers to Quantitative analysis of changes in Bcl-2 and Bax mRNA levels.…”

“…Ischemic stroke is one of the most common causes of mortality and morbidity worldwide [1]. It has been proposed that brain cells experience a dramatic reduction in blood supply during an ischemic stroke; this reduction diminishes their access to oxygen and glucose and induces the pathophysiological features of damaged cells, thereby promoting necrotic cell death [2][3][4].…”

Signaling Pathways in Cardiac Myocyte Apoptosis

“…The beneficial effect of p27 was mediated, at least in part, by activation of autophagy [243]. Interestingly, mice deficient in p21 or p27 have also been shown to be protected from some pathological conditions [244, 245]. This discrepancy may be explained by the fact that the mice used in these studies are germline knockout animals and thus many types of cells were affected instead of one single cell type.…”