Jun-Lin Jiang

Relationship between protective effects of rosiglitazone on endothelium and endogenous nitric oxide synthase inhibitor in streptozotocin-induced diabetic rats and cultured endothelial cells

Previous investigations have indicated that the level of asymmetric dimethylarginine (ADMA) is increased in diabetic patients and animals, and rosiglitazone has a protective effect on the endothelium. In the present study, we tested the relationship between protective effects of rosiglitazone and ADMA in streptozotocin (STZ)‐induced diabetic rats and cultured endothelial cells.

Accelerated onset of senescence of endothelial progenitor cells in patients with type 2 diabetes mellitus: role of dimethylarginine dimethylaminohydrolase 2 and asymmetric dimethylarginine.

The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1.

All-trans retinoic acid inhibits cobalt chloride-induced apoptosis in PC12 cells: Role of the dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine pathway

Previous studies have shown that the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its specific hydrolase dimethylarginine dimethylaminohydrolase (DDAH) are involved in the regulation of apoptosis in different cell types. In the present study, we investigated the role of the DDAH/ADMA pathway in cobalt chloride (CoCl2)–induced apoptosis and the antiapoptotic effect of all‐trans retinoic acid (atRA) in undifferentiated pheochromocytoma (PC12) cells. Treatment of CoCl2 (125 μM) for 48 hr significantly induced the apoptosis of PC12 cells, concomitantly with increased intracellular reactive oxygen species (ROS) production and caspase‐3 activity. CoCl2 treatment also decreased the activity of DDAH and the expression of DDAH2 (mRNA and protein), resulting in an increased level of ADMA. All these alterations induced by CoCl2 were attenuated by atRA (0.1, 1, or 10 μM). Interestingly, the antiapoptotic effects of atRA were inhibited by DDAH2 small RNA interference. In contrast, DDAH2 overexpression inhibited the proapoptotic effects of CoCl2. We also found that treatment of exogenous ADMA (3, 10, or 30 μM) induced the apoptosis of PC12 cells in a concentration‐ and time‐dependent manner, which was inhibited by the antioxidant or the caspase‐3 inhibitor. These findings suggest that the modulation of the DDAH/ADMA/ROS pathway plays an important role in CoCl2‐induced apoptosis and the antiapoptotic effects of atRA in undifferentiated PC12 cells.

Angiogenesis is a Link Between Atherosclerosis and Tumorigenesis: Role of LOX-1

Angiogenesis is defined as the formation of new blood vessels sprouting from pre-existing vessels. It plays an important role not only in physiological situations such as embryonic vascular development and wound healing, but also in pathological conditions including atherogenesis and evolution and spread of certain tumors. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low density lipoprotein (ox-LDL), is mainly expressed in endothelial cells. It has diverse physiological functions and it could be a link between atherogenesis and tumorigenesis. The risk factors for atherosclerosis like hypertension, diabetes mellitus and hyperlipidemia are associated with LOX-1. Dyslipidemia and obesity are also being recognized as risk factor for certain tumors. LOX-1 is also found to be important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth. There is emerging evidence that LOX-1 plays an important role in the angiogenesis process. In this review, we outline the roles of angiogenesis in atherogenesis and tumorigenesis, and describe the role of LOX-1 as a potential molecular target for blocking angiogenesis.

Involvement of DDAH/ADMA pathway in the pathogenesis of rheumatoid arthritis in rats.

Endothelial dysfunction is the early stage of atherosclerosis, which is typically associated with rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is not only an independent predictor for endothelial dysfunction but also a proinflammatory mediator. It has been shown that the level of ADMA was elevated in patients with RA. In the present study, we investigated the potential effect of ADMA on inflammation process in collagen-induced arthritis (CIA) animal model and primary cultured fibroblast-like synoviocytes (FLS) exposed to tumor necrosis factor-α (TNF-α). In CIA rats, the plasma levels of inflammatory cytokines TNF-α, interleukin-1β (IL-1β) and IL-6 were markedly increased, while the plasma levels of ADMA did not increase. The expression of dimethylarginine dimethylohydrolase2 (DDAH2), the key enzyme for ADMA degradation, was markedly reduced in inflamed joint synovium of CIA rats. Moreover, the expression of anti-inflammatory factor cortistatin (CST) was markedly decreased in joint synovium of CIA rats. Treatment of cultured FLS with TNF-α significantly increased the levels of ADMA, and decreased the expression of DDAH2 mRNA and protein accompany with an increase in the levels of IL-1β and IL-6 and a reduction in the expression of CST mRNA and protein, and the effects of TNF-α were abolished by DDAH2 overexpression. Treatment of FLS with ADMA also significantly increased the levels of IL-1β and IL-6, and reduced the expression of CST. These findings suggest that DDAH/ADMA participates in the pathogenesis of RA, and that the effect of DDAH/ADMA may be mediated by CST.

Dimethylarginine dimethylaminohydrolase 1 regulates nerve growth factor-promoted differentiation of PC12 cells in a nitric oxide-dependent but asymmetric dimethylargenine-independent manner

There are significant morphological and biochemical alterations during nerve growth factor (NGF)‐promoted neuronal differentiation, and the process is regulated by molecules, including nitric oxide (NO). Dimethylarginine dimethylaminohydrolase (DDAH) is thought to play a critical role in regulating NO production via hydrolyzing the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Thus, we tested the role of DDAH in NGF‐promoted differentiation of PC12 (pheochromocytoma) cells. The present results show that both mRNA and protein levels of DDAH1 were increased, whereas those of DDAH2 were decreased, during NGF‐promoted cell differentiation. Both the DDAH activity and the ADMA level in cultured medium were unchanged in this process. NGF promoted neurite formation and induced the expression of microtubule‐associated protein 2 (MAP2), a neuronal marker, which were both significantly repressed by DDAH1 silence with small interfering RNA but not by DDAH2 silence. The expressions of three isoforms of NOS were markedly upregulated after NGF stimulation with a time course similar to that of DDAH1, which were attenuated by DDAH1 silence. Conversely, overexpression of DDAH1 accelerated neurite formation in PC12 cells, concomitantly with upregulating the expression of three NOS isoforms. In summary, our data reveal the critical regulatory effect of DDAH1 on NGF‐promoted differentiation of PC12 cells in an NOS/NO‐dependent but ADMA‐independent manner.

Cardiovascular risk in autoimmune disorders: Role of asymmetric dimethylarginine

Mounting evidence indicates that cardiovascular events are a main cause of excessive mortality of autoimmune disorders like type I diabetes mellitus and rheumatic diseases. Inflammation and endothelial dysfunction, independent predictors to cardiovascular disease, are hallmarks of autoimmunity. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, can cause or contribute to the inflammatory syndrome and endothelial dysfunction. Recently, elevated ADMA levels have been demonstrated in many autoimmune diseases, suggesting that ADMA might play an important role for the associated manifestations of cardiovascular disease. In the review, we discuss the role of ADMA in the excessive cardiovascular morbidity and mortality associated with autoimmune diseases.

Discoidin domain receptors (DDRs): Potential implications in atherosclerosis

Atherosclerosis, one of the most common causes of cardiovascular diseases, is associated with a high morbidity and mortality. It is known that inflammation, vascular smooth muscle cell (VSMCs) phenotypic modulation and atheroma plaque vulnerability are main pathological characteristics of atherosclerosis. The discoidin domain receptors (DDRs), as unique collagen-binding tyrosine kinase receptors, were reported to be involved in the above pathogenesis process of atherogenesis. DDRs were detected on a series of cells within atherosclerotic plaques including macrophages, T cells and smooth muscle cells, and regulated the behaviors of these cells, implicating the potential involvement of DDRs in atherosclerosis. Herein we discuss the roles of DDRs in atherosclerosis, in an attempt to evaluate the value of DDRs as a therapeutic target for atherosclerosis.

Role of Asymmetrical Dimethylarginine in Diabetic Microvascular Complications.

Abstract: Microvascular complications are the leading causes of acquired blindness, end-stage renal failure, and varieties of neuropathy associated with diabetes. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is involved in endothelial dysfunction, oxidative stress, and inflammation associated with the progression of diabetic microvascular complications. Elevated ADMA has been detected in experimental animals and patients with diabetic microangiopathy like retinopathy, nephropathy, and neuropathy. In the review, we focus on the role of ADMA in the pathobiology of major microvascular complications of diabetes.

The Protective Effects of Monophosphoryl Lipid A on the Ischemic Myocardium and Endothelium in Rats

Previous investigations have shown that a single dose of low-density lipoprotein (LDL) injection causes a marked decrease in endothelium-dependent relaxation, and that endothelial dysfunction aggravates myocardial injury due to ischemia-reperfusion in atherosclerotic animals. Monophosphoryl lipid A-induced delayed preconditioning preserves the ischemic myocardium and endothelial cells. The objective of the present study was to examine the effect of monophosphoryl lipid A on endothelial function and ischemia-reperfusion-induced myocardial injury in the rats treated with LDL. A single injection of native LDL (4 mg/kg, i.v.) caused a significant decrease in vasodilator responses to acetylcholine and an increase in the serum level of asymmetric dimethylarginine, the endogenous nitric oxide synthase inhibitor. Pretreatment with monophosphoryl lipid A (300 or 450 μg/kg, i.p.) significantly improved endothelium-dependent relaxation and decreased concentrations of asymmetric dimethylarginine, and the effects of monophosphoryl lipid A were attenuated by L-nitro-arginine-methylester, but not by aminoguanidine. LDL treatment only aggravated the decreased coronary flows but did not affect cardiac dysfunction due to ischemia-reperfusion in the rats treated with LDL. Pretreatment with monophosphoryl lipid A significantly improved cardiac dysfunction by ischemia-reperfusion in the rats treated with or without LDL, an effect that was abolished by aminoguanidine. The present study suggests that: (1) a single injection of native LDL causes a decrease in endothelium-dependent relaxation, and aggravates the decrease of coronary flow due to ischemia-reperfusion, (2) pretreatment with monophosphoryl lipid A protects the myocardium against ischemia-reperfusion in the rats treated with or without native LDL, and (3) the protective effect of monophosphoryl lipid A on endothelial cells is related to reduction of asymmetric dimethylarginine level.