Knockdown of CCM3 promotes angiogenesis through activation and nuclear translocation of YAP/TAZ.

Angiogenesis, a finely regulated process, plays a crucial role in the progression of various diseases. Cerebral cavernous malformation 3 (CCM3), alternatively referred to as programmed cell death 10 (PDCD10), stands as a pivotal functional gene with a broad distribution across the human body. However, the precise role of CCM3 in angiogenesis regulation has remained elusive. YAP/TAZ, as core components of the evolutionarily conserved Hippo pathway, have garnered increasing attention as a novel mechanism in angiogenesis regulation. Nonetheless, whether CCM3 regulates angiogenesis through YAP/TAZ mediation has not been comprehensively explored. In this study, our primary focus centers on investigating the regulation of angiogenesis through CCM3 knockdown mediated by YAP/TAZ. Silencing CCM3 significantly enhances the proliferation, migration, and tubular formation of human umbilical vein endothelial cells (HUVECs), thereby promoting angiogenesis. Furthermore, we observe an upregulation in the expression levels of VEGF and VEGFR2 within HUVECs upon silencing CCM3. Mechanistically, the evidence we provide suggests for the first time that endothelial cell CCM3 knockdown induces the activation and nuclear translocation of YAP/TAZ. Finally, we further demonstrate that the YAP/TAZ inhibitor verteporfin can reverse the pro-angiogenic effects of siCCM3, thereby confirming the role of CCM3 in angiogenesis regulation dependent on YAP/TAZ. In summary, our findings pave the way for potential therapeutic targeting of the CCM3-YAP/TAZ signaling axis as a novel approach to promote angiogenesis.

Urolithin A alleviates myocardial ischemia/reperfusion injury via PI3K/Akt pathway.

Ischemia/reperfusion (I/R) induces additional damage to the restoration of blood flow to ischemic myocardium. This study examined the effects of urolithin A (UA) on myocardial injury of ischemia/reperfusion in vivo and vitro and explored its underlying mechanisms. Mice were subjected to myocardial ischemia followed by reperfusion. Cells were subjected to hypoxia followed by reoxygenation. UA alleviated hypoxia/reoxygenation (H/R) injury in myocardial cells, reduced myocardial infarct size and cell death in mice after ischemia/reperfusion. Meanwhile, UA enhanced antioxidant capacity in cardiomyocytes following hypoxia/reoxygenation. UA reduced myocardial apoptosis following ischemia/reperfusion. The protection of UA was abolished by LY294002, a PI3K/Akt-inhibitor. These results demonstrated that UA alleviates myocardial ischemia/reperfusion injury probably through PI3K/Akt pathway.

Pramipexole pretreatment attenuates myocardial ischemia/reperfusion injury through upregulation of autophagy.

This article investigated the effects of pramipexole on myocardial ischemia reperfusion (I/R) injury and its underlying mechanisms. We utilized an in vivo mouse model of myocardial I/R injury and an in vitro H9c2 cell model of hypoxia/reoxygenation (H/R) injury. Pramipexole pretreatment in male C57BL/6 mice significantly reduced the myocardial infarction size, decreased the CK and LDH activities at the serum level and enhanced autophagy. In the in vitro study, the pramipexole treatment significantly elevated the survival rate, decreased the LDH activity, reduced ROS generation and restored the ΔΨm in H9C2 cells during H/R. Additionally, its use could increase the autophagy flux level in H9c2 cells. The underlying mechanisms were determined by measuring the expression of the autophagic protein levels. These results further indicated that pramipexole treatment modulated H/R-induced autophagy via an AMPK-dependent pathway. All of these data indicate that pramipexole exerted protective effects against myocardial I/R injury and enhanced autophagy in part through the AMPK-mediated pathway.

Dexpramipexole attenuates myocardial ischemia/reperfusion injury through upregulation of mitophagy.

Reperfusion causes undesirable damage to the ischemic myocardium while restoring the blood flow. In this study, we evaluated the effects of dexpramipexole (DPX) on myocardial injury induced by ischemia/reperfusion (I/R) in-vivo and the hypoxia/reoxygenation (HR) in-vitro and examined the functional mechanisms of DPX. DPX protected cells against H/R-induced mitochondrial dysfunction and prevented H/R damage. Both myocardial infarct size and tissue damage due to I/R was reduced upon DPX treatment. We discovered that DPX enhanced mitophagy in-vivo and in-vitro, which was accompanied by enhanced expression of PINK1 and Parkin. Knock-down of PINK1 and Parkin by specific siRNAs reversed DPX-induced inhibition of myocardial I/R injury. These findings suggest that DPX might protect against myocardial injury via PINK1 and Parkin.

Polydatin inhibits the oxidative stress-induced proliferation of vascular smooth muscle cells by activating the eNOS/SIRT1 pathway.

Oxidative stress-mediated proliferation of vascular smooth muscle cells (VSMCs) contributes to plaque formation and the progression of atherosclerosis. Polydatin is a derivative of resveratrol, and is widely present in certain herbal medications used for the treatment of cardiovascular diseases. In the present study, we examined whether polydatin was capable of attenuating VSMC proliferation induced by oxidative stress as well as the potential involvement of the endothelial nitric oxide synthetase (eNOS)/SIRT1 pathway. Briefly, VSMCs were exposed to H2O2 for 24 h in the absence or presence of polydatin (10-100 µM) prior to performing a cell proliferation assay. In mechanistic studies, the cells were incubated with the silent information regulator 1 (SIRT1) inhibitor, EX527, or the eNOS inhibitor, L-NAME, prior to polydatin treatment. The results showed that polydatin inhibited VSMC proliferation and the level of reactive oxygen species, increased the expression of Kip1/p27, SIRT1 and eNOS, whereas the expression of cyclin B1, Cdk1 and c-myc was decreased. The number of cells in the G2/M phase was increased. Pre-treatment with L-NAME attenuated the inhibitory effects of polydatin on cell proliferation, inhibited the expression of SIRT1 and the phosphorylation of eNOS. Pre-treatment with EX527 also attenuated the inhibitory effects of polydatin on cell proliferation, but failed to reduce the activation of eNOS and the production of nitric oxide. Taken together, these findings suggest that, polydatin inhibited the oxidative stress-induced proliferation of VMSCs by activating the eNOS/SIRT1 pathway.