scholarly journals Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

2013 ◽  
Vol 304 (2) ◽  
pp. E222-E228 ◽  
Author(s):  
Zhenhua Dong ◽  
Weidong Chai ◽  
Wenhui Wang ◽  
Lina Zhao ◽  
Zhuo Fu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Microvascular Blood Flow ◽  
No Production ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Microvascular Recruitment ◽  
Kinase A

Glucagon-like peptide-1 (GLP-1) causes vasodilation and increases muscle glucose uptake independent of insulin. Recently, we have shown that GLP-1 recruits muscle microvasculature and increases muscle glucose use via a nitric oxide (NO)-dependent mechanism. Protein kinase A (PKA) is a major signaling intermediate downstream of GLP-1 receptors. To examine whether PKA mediates GLP-1's microvascular action in muscle, GLP-1 was infused to overnight-fasted male rats for 120 min in the presence or absence of H89, a PKA inhibitor. Hindleg muscle microvascular recruitment and glucose use were determined. GLP-1 infusion acutely increased muscle microvascular blood volume within 30 min without altering microvascular blood flow velocity or blood pressure. This effect persisted throughout the 120-min infusion period, leading to a significant increase in muscle microvascular blood flow. These changes were paralleled with an approximately twofold increase in plasma NO levels and hindleg glucose extraction. Systemic infusion of H89 completely blocked GLP-1-mediated muscle microvascular recruitment and increases in NO production and muscle glucose extraction. In cultured endothelial cells, GLP-1 acutely increased PKA activity and stimulated endothelial NO synthase phosphorylation at Ser1177 and NO production. PKA inhibition abolished these effects. In ex vivo studies, perfusion of the distal saphenous artery with GLP-1 induced significant vasorelaxation that was also abolished by pretreatment of the vessels with PKA inhibitor H89. We conclude that GLP-1 recruits muscle microvasculature by expanding microvascular volume and increases glucose extraction in muscle via a PKA/NO-dependent pathway in the vascular endothelium. This may contribute to postprandial glycemic control and complication prevention in diabetes.

Protein kinase A activation is required for IL-1-induced nitric oxide production by cardiac myocytes

1996 ◽  
Vol 271 (1) ◽  
pp. C429-C434 ◽  
Author(s):  
C. V. Oddis ◽  
R. L. Simmons ◽  
B. G. Hattler ◽  
M. S. Finkel
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cardiac Myocytes ◽  
Interleukin 1 ◽  
Neonatal Rat ◽  
Inos Mrna ◽  
No Production ◽  
Neonatal Rat Cardiac Myocytes ◽  
Kinase A

We have previously reported that interleukin-1 beta (IL-1) alone induced the transcription of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production by isolated neonatal rat cardiac myocytes (CM). The present studies were undertaken to explore the signal transduction pathways involved in IL-1-induced NO production by CM. The addition of IL-1 to CM resulted in a peak rise in both adenosine 3',5'-cyclic monophosphate (cAMP) and protein kinase A (PKA) activities by 10 min followed by rapid declines and return to basal levels within 60 min. The PKA inhibitor KT-5720 completely blocked NO-2 production by IL-1-stimulated CM (P < 0.01; n = 12). The protein kinase C (PKC) inhibitor, calphostin C, had no effect on NO2- production by IL-1 stimulated CM [P = not significant (NS); n = 12]. The addition of PKA+cAMP to cytosols derived from IL-1-treated CM did not directly enhance iNOS enzyme activity (P = NS; n = 3). CM treated with IL-1 alone stained positively for iNOS protein by immunohistochemistry. iNOS staining was absent in CM treated with IL-1+KT-5720. KT-5720 resulted in an earlier disappearance of iNOS mRNA from IL-1-treated CM, as detected by semiquantitative reverse transcriptase-polymerase chain reaction. We report for the first time that PKA (but not PKC) activation is required for IL-1-induced NO production by CM.

Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A

2012 ◽  
Vol 84 (3) ◽  
pp. 395-398 ◽  
Author(s):  
Yuji Ishibashi ◽  
Takanori Matsui ◽  
Ayako Ojima ◽  
Yuri Nishino ◽  
Sae Nakashima ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mesangial Cell ◽  
Cell Damage ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Kinase A

Leptin-induced nitric oxide production in white adipocytes is mediated through PKA and MAP kinase activation

2005 ◽  
Vol 289 (2) ◽  
pp. C379-C387 ◽  
Author(s):  
Nadia Mehebik ◽  
Anne-Marie Jaubert ◽  
Dominique Sabourault ◽  
Yves Giudicelli ◽  
Catherine Ribière
Keyword(s):  
Nitric Oxide ◽  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Phosphatase ◽  
Plasma Levels ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Tyrosine Kinase 2 ◽  
Kinase A

Leptin injection increases plasma levels of nitrites and/or nitrates, an index of nitric oxide (NO) production. Because plasma levels of NO are correlated with fat mass and because adipose tissue is the main source of leptin, it seems that adipose tissue plays a major role in NO release induced by leptin. Adipocytes express both leptin receptors and nitric oxide synthase (NOS; including the endothelial isoform, NOS III, and the inducible isoform, NOS II). In this study, we have demonstrated that physiological concentrations of leptin stimulate NOS activity in adipocytes. This effect of leptin is abolished by 1) AG490, an inhibitor of Janus tyrosine kinase 2/signal transducer and activator of transcription 3; 2) U0126, an inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (p42/p44 MAPK); and 3) N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) or Rp diastereomer of adenosine 3′,5′-cyclic phosphorothioate, two inhibitors of protein kinase A, but not by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Immunoblotting studies have shown that leptin fails to activate Akt but increases p42/p44 MAPK phosphorylation, an effect that is prevented by U0126 but not by H-89. Furthermore, leptin induces NOS III phosphorylation at Ser1179and Thr497, but not when adipocytes are pretreated with H-89 or U0126. Finally, stimulation of adipocyte NOS activity by leptin is either unaltered when protein phosphatase 2A is inhibited by 1 nM okadaic acid or completely abolished when protein phosphatase 1 (PP1) activity is inhibited by 3 nM tautomycin, which supports a crucial role for PP1 in mediating this effect of leptin. On the whole, these experiments demonstrate that NOS activity is a novel target for leptin in adipocytes and that the leptin-induced NOS activity is at least in part the result of NOS III phosphorylations via both protein kinase A and p42/p44 MAPK activation. More generally, this study also leads to the hypothesis of NO as a potentially important factor for leptin signaling in adipocytes.

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