The Roles of AMPK in Revascularization.

Coronary heart disease (CHD) is the most common and serious illness in the world and has been researched for many years. However, there are still no real effective ways to prevent and save patients with this disease. When patients present with myocardial infarction, the most important step is to recover ischemic prefusion, which usually is accomplished by coronary artery bypass surgery, coronary artery intervention (PCI), or coronary artery bypass grafting (CABG). These are invasive procedures, and patients with extensive lesions cannot tolerate surgery. It is, therefore, extremely urgent to search for a noninvasive way to save ischemic myocardium. After suffering from ischemia, cardiac or skeletal muscle can partly recover blood flow through angiogenesis (de novo capillary) induced by hypoxia, arteriogenesis, or collateral growth (opening and remodeling of arterioles) triggered by dramatical increase of fluid shear stress (FSS). Evidence has shown that both of them are regulated by various crossed pathways, such as hypoxia-related pathways, cellular metabolism remodeling, inflammatory cells invasion and infiltration, or hemodynamical changes within the vascular wall, but still they do not find effective target for regulating revascularization at present. 5'-Adenosine monophosphate-activated protein kinase (AMPK), as a kinase, is not only an energy modulator but also a sensor of cellular oxygen-reduction substances, and many researches have suggested that AMPK plays an essential role in revascularization but the mechanism is not completely understood. Usually, AMPK can be activated by ADP or AMP, upstream kinases or other cytokines, and pharmacological agents, and then it phosphorylates key molecules that are involved in energy metabolism, autophagy, anti-inflammation, oxidative stress, and aging process to keep cellular homeostasis and finally keeps cell normal activity and function. This review makes a summary on the subunits, activation and downstream targets of AMPK, the mechanism of revascularization, the effects of AMPK in endothelial cells, angiogenesis, and arteriogenesis along with some prospects.

Acid Sphingomyelinase Mediates Oxidized-LDL Induced Apoptosis in Macrophage via Endoplasmic Reticulum Stress.

AIM: Macrophage apoptosis is a vital event in advanced atherosclerosis, and oxidized low-density lipoprotein (ox-LDL) is a major contributor to this process. Acid sphingomyelinase (ASM) and ceramide are also involved in the induction of apoptosis, particularly in macrophages. Our current study focuses on ASM and investigates its role in ox-LDL-induced macrophage apoptosis. METHODS: Human THP-1 and mouse peritoneal macrophages were cultured in vitro and treated with ox-LDL. ASM activity and ceramide levels were quantified using ultra performance liquid chromatography. Protein and mRNA levels were analyzed using Western blot analysis and quantitative real-time PCR, respectively. Cell apoptosis was determined using Hoechst staining and flow cytometry. RESULTS: Ox-LDL-induced macrophage apoptosis was triggered by profound endoplasmic reticulum (ER) stress, leading to an upregulation of ASM activity and ceramide levels at an early stage. ASM was inhibited by siRNA or desipramine (DES), and/or ceramide was degraded by recombinant acid ceramidase (AC). These events attenuated the effect of ox-LDL on ER stress. In contrast, recombinant ASM upregulated ceramide and ER stress. ASM siRNA, DES, recombinant AC, and ER stress inhibitor 4-phenylbutyric acid were blocked by elevated levels of C/EBP homologous protein (CHOP); ox-LDL induced elevated levels of CHOP. These events attenuated macrophage apoptosis. CONCLUSION: These results indicate that ASM/ceramide signaling pathway is involved in ox-LDL-induced macrophage apoptosis via ER stress pathway.

Demethylbellidifolin prevents nitroglycerin tolerance via improved aldehyde dehydrogenase 2 activity.

The aim of this study was to investigate the effect of demethylbellidifolin (DMB), a major xanthone compound of Swertia davidi franch, on nitroglycerin (NTG) tolerance. In the in vivo portion of the study, pretreatment of Sprague-Dawley rats with NTG (10 mg/kg) for 8 days caused tolerance to the depressor effect of NTG. This was evident because the depressor effect of NTG (150 microg/kg, I. V.) was almost completely abolished in the tolerant rats. The tolerance could be diminished by treatment with DMB. In the in vitro study, the exposure of aortic rings of Sprague-Dawley rats to NTG (10 microM) for 30 min caused tolerance to the vasodilating effect of NTG. The tolerance is evident because of a substantial right shift of the NTG concentration-relaxation curves. This shift was reduced by pretreatment of the aortic rings with DMB. In cultured human umbilical vein endothelial cells (HUVECs), incubation of NTG for 16 h increased reactive oxygen species (ROS) production, attenuated cyclic guanosine monophosphate (cGMP) levels and decreased the activity of aldehyde dehydrogenase 2 (ALDH-2), the main enzyme responsible for NTG bioactivation. All the effects mentioned above were prevented by co-incubation with DMB. In conclusion, DMB prevents NTG tolerance via increasing ALDH-2 activity through decreasing ROS production.

Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, has been implicated in vascular inflammation through induction of reactive oxygen species (ROS) and proinflammatory genes in endothelial cells. However, relatively few attentions have been paid to the effect of ADMA on monocytes, one of the important cells throughout all stages of atherosclerosis. In the present study, we found that reinioside C, the main component extracted from Polygala fallax Hemsl., dose-dependently inhibited tumor necrosis factor-alpha (TNF-alpha) production induced by ADMA in monocytes, Furthermore, reinioside C attenuated ADMA-induced generation of reactive oxygen species and activation of nuclear factor-kappaB (NF-kappaB) activity in monocytes in a dose-dependent manner, this effect was inhibited by l-arginine (NOS substrate) and PDTC (inhibitor of NF-kappaB). These data suggest that reinioside C could attenuate the increase of TNF-alpha induced by exogenous ADMA through inhibition ROS/NF-kappaB pathway in monocytes.