Probucol Protects Against Asymmetric Dimethylarginine-Induced Apoptosis in the Cultured Human Brain Microvascular Endothelial Cells

Abstract

Asymmetric dimethylarginine (ADMA) is emerging as a key contributor to endothelial dysfunction. The drug probucol was reported to have an anti-lipid peroxidation effect and improve endothelial dilation function. But little is known about the protective effect of probucol on ADMA-induced human brain microvascular endothelial cell (HBMEC) injury and its underlying mechanisms. Therefore, in this study, we investigated the effect of probucol on ADMA-induced HBMEC injury and its potential mechanisms. Results showed that probucol protected against ADMA-induced HBMEC injury in a dose-dependent manner; probucol pretreatment also significantly reduced the level of reactive oxygen species (ROS) and malondialdehyde (MDA), downregulated the expression of pro-apoptotic gene Bax and caspase-3 activity, as well as increased the brain-derived neurotrophic factor (BDNF) release and promoted anti-apoptotic gene Bcl-2 and eNOS expression in the cultured HBMECs. Furthermore, we found that ADMA significantly increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38, while probucol pretreatment effectively inhibited ADMA-induced JNK and p38 phosphorylation in HBMECs. In conclusion, our present results demonstrated that probucol protected against ADMA-induced HBMEC injury and suppressed oxidative stress through the JNK/p38 MAPK pathway, which was the potential underlying mechanism of HBMEC injury in ischemic cerebrovascular disease.

Brain‐derived neurotrophic factor of the cerebral microvasculature: a forgotten and nitric oxide‐dependent contributor of brain‐derived neurotrophic factor in the brain

“…Our present results revealing the opposite effect of exercise and hypertension on both cerebrovascular BDNF and P-eNOS ser1177 and a stimulating effect of an NO donor on cerebrovascular BDNF production argue for an in vivo control of cerebrovascular BDNF production by NO derived from cerebral endothelium. These data resonate with studies that reported lower BDNF levels in cultured microvascular endothelial cells exposed to the endogenous eNOS inhibitor asymmetric dimethyl arginine (ADMA) (Ma et al 2015) or to advanced glycosylation products (Navaratna et al 2011), which act as NO scavengers (Bucala et al 1991). They also could explain the reduction of brain BDNF levels reported after genetic and pharmacological eNOS inhibition (Chen et al 2005, Banoujaafar et al 2014.…”

“…These data resonate with studies that reported lower BDNF levels in cultured microvascular endothelial cells exposed to the endogenous eNOS inhibitor asymmetric dimethyl arginine (ADMA) (Ma et al . ) or to advanced glycosylation products (Navaratna et al . ), which act as NO scavengers (Bucala et al .…”

Probucol Prevents Diabetes-Induced Retinal Neuronal Degeneration through Upregulating Nrf2

“…e antioxidant and anti-inflammatory properties of probucol have been investigated using in vitro cell cultures and in vivo animal models [13,14]. It inhibits extracellular ROS and effectively reduces vascular endothelial cell apoptosis caused by oxidative stress damage [25]. Probucol reduces hypoxia-induced angiogenesis by improving the function of endothelial progenitor cells [26].…”

The Cerebral Brain-Derived Neurotrophic Factor Pathway, Either Neuronal or Endothelial, Is Impaired in Rats with Adjuvant-Induced Arthritis. Connection with Endothelial Dysfunction

“…Notably, a positive control by endothelium-derived NO of BDNF synthesis by cerebral endothelial cells is not surprising. Indeed, the exposure of cultured brain-derived endothelial cells to inhibitors of NO production including the peptide A beta (a compound largely involved in the physiopathology of Alzheimer disease) and ADMA (an endogenous eNOS inhibitor) was reported to decrease BDNF production (Guo et al, 2008 ; Ma et al, 2015 ). In the same vein, incubation of isolated cerebral microvessels with advanced glycation-end products (Navaratna et al, 2011 ) that act as NO scavengers (Bucala et al, 1991 ) resulted in BDNF downregulation whilst their incubation with a slow releasing NO donor was recently reported by our laboratory to increase BDNF production (Monnier et al, 2017b ).…”