Aortic dissection and aneurysm are associated with abnormal hemodynamic loads originating from hypertension. Our previous study demonstrated that cyclic mechanical stretch (CMS, mimicked ...hypertension) caused the death of rat aortic smooth muscle cells (RASMCs) in a mitogen activated-protein kinases (MAPKs)-dependent manner. The current study investigated the effects of inducible nitric oxide synthase (iNOS) on CMS-induced RASMC death. cDNA microarrays for CMS-treated RASMCs showed that iNOS expression levels were increased in response to CMS. Real-time polymerase chain reaction (PCR) analysis demonstrated that this increase was p38 MAPK (p38)-dependent. NO production was also increased. This increase could be inhibited by p38 and iNOS inhibitors. Thus, CMS-induced iNOS synthesized NO. CMS-induced cell death in RASMCs was increased by the iNOS inhibitor but abrogated by the long-acting NO donor DETA-NONOate. Increased iNOS expression was confirmed in the abdominal aortic constriction mouse model. Signal transducers and activators of transcription 1 (STAT1) was activated in stretched RASMCs, and iNOS expression and NO production were inhibited by the STAT1 inhibitor nifuroxazide. Our findings suggest that RASMCs were protected by iNOS from CMS-stimulated cell death through the STAT1 and p38 signal pathways independently.
In mammals, amino acid metabolism has evolved to act as a critical regulator of innate and adaptive immune responses. Rheumatoid arthritis (RA) is the most common form of inflammatory arthropathy ...sustained by autoimmune responses. We examine here the current knowledge of tryptophan and arginine metabolisms and the main immunoregulatory pathways in amino acid catabolism, in both RA patients and experimental models of arthritis. We found that l-tryptophan (Trp) metabolism and, in particular, the kynurenine pathway would exert protective effects in all experimental models and in some, but not all, RA patients, possibly due to single nucleotide polymorphisms in the gene coding for indoleamine 2,3-dioxygenase 1 (IDO1; the enzyme catalyzing the rate-limiting step of the kynurenine pathway). The function, i.e., either protective or pathogenetic, of the l-arginine (Arg) metabolism in RA was less clear. In fact, although immunoregulatory arginase 1 (ARG1) was highly induced at the synovial level in RA patients, its true functional role is still unknown, possibly because of few available preclinical data. Therefore, our analysis would indicate that amino acid metabolism represents a fruitful area of research for new drug targets for a more effective and safe therapy of RA and that further studies are demanding to pursue such an important objective.
Benefits of L-Arginine on Cardiovascular System Sudar-Milovanovic, Emina; Obradovic, Milan; Jovanovic, Aleksandra ...
Mini reviews in medicinal chemistry,
01/2016, Letnik:
16, Številka:
2
Journal Article
Recenzirano
The amino acid, L-Arginine (L-Arg) plays an important role in the cardiovascular system. Data from the literature show that L-Arg is the only substrate for the production of nitric oxide (NO), from ...which L-Arg develops its effects on the cardiovascular system. As a free radical, NO is synthesized in all mammalian cells by L-Arg with the activity of NO synthase (NOS). In states of hypertension, diabetes, hypercholesterolemia and vascular inflammation a disorder occurs in the metabolic pathway of the synthesis of NO from L-Arg which all together bring alterations of blood vessels. Experimental results obtained on animals, as well as clinical studies show that L-Arg has an effect on thrombocytes, on the process of coagulation and on the fibrolytic system. This mini review represents a summary of the latest scientific animal and human studies related to L-Arg and its mechanisms of actions with a focus on the role of L-Arg via NO pathway in cardiovascular disorders. Moreover, here we present data from recent animal and clinical studies suggesting that L-Arg could be one of the possible therapeutic molecules for improving the treatment of different cardiovascular disorders.
The objective of the study was to characterize expression patterns of hypoxia‐inducible factor‐1alpha (HIF1A), inducible nitric oxide synthase (iNOS) and endothelial (eNOS) isoforms in time‐defined ...follicle classes before and after GnRH application in the cow. Ovaries containing pre‐ovulatory follicles or corpora lutea were collected by transvaginal ovariectomy (n = 5 cows/group) as follow: (I) before GnRH administration; (II) 4h after GnRH; (III) 10h after GnRH; (IV) 20h after GnRH; (V) 25h after GnRH; and (VI) 60h after GnRH (early corpus luteum). The mRNA abundance of HIF1A in the follicle group before GnRH was high, followed by a significant down regulation afterwards with a minimum level 25h after GnRH (close to ovulation) and significant increase only after ovulation. The mRNA abundance of iNOS before GnRH was high, decreased significantly during LH surge, with minimum levels afterwards. In contrast, the mRNA of eNOS decreased in the follicle group 20h after GnRH, followed by a rapid and significant upregulation just after ovulation. Immunohistochemically, the granulosa cells of antral follicles and the eosinophils of the theca tissue as well of the early corpus luteum showed a strong staining for HIF1A. The location of the eosinophils could be clearly demonstrated by immunostaining with an eosinophil‐specific antibody (EMBP) and transmission electron microscopy. In conclusion, the parallel and acute regulated expression patterns of HIF1A and NOS isoforms, specifically during the interval between the LH surge and ovulation, indicate that these paracrine factors are involved in the local mechanisms, regulating final follicle maturation, ovulation and early luteal angiogenesis.
There is good evidence that nitric oxide has important autocrine/paracrine effects in the myocardium, serving to optimise and fine tune cardiac function
Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial ...nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150–200 g, 10–12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)
–1
) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg
–1
, subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (
L
-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.
In healthy condition, vascular smooth muscle cells (VSMCs) are not directly exposed to shear stresses, because they are shielded by endothelial cell (EC) layer that lines blood vessels. After injury ...to EC layer caused by rupture of atherosclerotic lesions or invasive techniques such as angioplasty, VSMCs are directly exposed to blood flow which modulate molecular signaling and function. In endothelium, exposure to fluid shear stress has been reported to induce AMP-activated protein kinase (AMPK) phosphorylation and nitric oxide (NO) production. However, the influence of laminar shear stress on exposed VSMC is not defined. In this study, we investigated whether laminar shear stress regulates AMPK phosphorylation in VSMC and tried to identify underlying signaling pathway. NO production was increased by shear stress. The expression of NOS isoforms was increased 1 h after exposure to shear stress, and AMPK phosphorylation started to increase after 2 h. AMPK and LKB1, the upstream kinases of AMPK, phosphorylation were decreased by the non-selective NOS inhibitor l-NAME and the selective iNOS inhibitor aminoguanidine despite exposure to shear stress. On the other hand, compound C, a specific AMPK inhibitor, did not affect the expression of NOS isoforms. In addition, PDGF-induced VSMC proliferation was decreased by shear stress and restored by l-NAME. These findings suggest that shear stress upregulated AMPK phosphorylation in VSMC via NOS expression may be a beneficial route to prevent pathogenesis in the vascular system.
•After endothelial injury, VSMCs are exposed to blood flow which modulate signaling.•In VSMCs, laminar shear stress directly induces NO production and AMPK activation.•LKB1 and AMPK phosphorylation were decreased by NOS inhibitor.•AMPK inhibitor, compound C, did not affect the expression of NOS isoforms.•Shear stress-AMPK activation in VSMC prevent pathogenesis in the vascular system.
Thyroid hormones (TH) play a critical role in ovarian follicular development, maturation and the maintenance of various endocrine functions. However, whether TH can affect ovarian follicular ...development in neonatal and immature rats remains unclear. Therefore, the aim of the present study was to elucidate the effect of TH on ovarian follicular development in neonatal and immature rats. Thirty female post-lactation mothers of Sprague–Dawley rat pups were randomly divided into three groups: control, hyperthyroid (hyper), and hypothyroid (hypo). On postnatal days (PND) 10 and 21, body weights, serum hormones, ovarian histologic changes, and immunohistochemistry of thyroid hormone receptor alpha 1 (TRα1) and nitric oxide synthase types (NOS), and NOS activities, were determined. The data showed that body weights significantly decreased in both hyper and hypo groups compared with the control group (
P
< 0.05). In addition, the hyper group had increased serum concentrations of T3, T4, and E2; whereas the hypo group manifested reduced serum concentrations of T3, T4, and E2 on PND 10 and 21. The hyper and hypo groups showed significantly reduced total number of primordial, primary and secondary follicles on PND 10 and 21 compared with the control group (
P
< 0.05). Similarly, antral follicle numbers in the hyper and hypo groups were significantly decreased on PND 21 compared with the control group (
P
< 0.05). Immunostaining indicated that TRα1 and NOS were expressed in ovarian surface epithelium and oocytes of growing and antral follicles, with strong staining of the granulosa and theca cells of follicles. NOS activities were significantly augmented in the hyper, but diminished in the hypo groups on PND 10 and 21. In summary, our findings suggest that TH play important roles in ovarian functions and in the regulation of NOS activity. Our results also indicate that a relationship exists between the TH and NO signaling pathways during the process of ovarian follicular development in neonatal and immature rats.
•Nitric oxide pathway is important for normal functioning of the heart.•Its dyregulation contributes to various cardiovascular diseases including DCM.•Potential role of epigenetic mechanisms in ...dysregulation of NOS pathway in DCM.•Understanding regulation of NOS may help create effective therapeutics for DCM.
Cardiovascular complications associated with diabetes significantly contribute to high mortality and morbidity worldwide. The pathophysiology of diabetic cardiomyopathy (DCM), although extensively researched upon, is partially understood. Impairment in various signaling pathways including nitric oxide (NO) signaling has been implicated in the pathogenesis of diabetes induced myocardial damage. Nitric oxide synthases (NOS), the enzymes responsible for NO generation, play an important role in various physiological processes. Altered expression and activity of NOS have been implicated in cardiovascular diseases, however, the role of NOS and their regulation in the pathogenesis of DCM remain poorly understood. In the present review, we focus on the role of myocardial NOS in the development of DCM. Since epigenetic modifications play an important role in regulation of gene expression, this review also describes the epigenetic regulation of NOS.
PDF
