Possible role of exogenous cAMP to improve vascular endothelial dysfunction in hypertensive rats

Shah, Dhvanit I.; Singh, Manjeet

doi:10.1111/j.1472-8206.2006.00449.x

Cited by 11 publications

(11 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, Br-cAMP or Db-cAMP pretreatment to cells led to significant reversal of CRP-mediated inhibition of GTPCH1 activity (Fig 3c). Furthermore, eNOS dysfunction has been reported to be attenuated via cAMP/PKA pathway activation [31,32]. The pretreatment of HAECs with cAMP analogues led to significant reversal of CRP-mediated eNOS inhibition (Fig 3d and e) in the present study.…”

Section: Resultssupporting

confidence: 58%

“…In this context, cell permeable analogue of cAMP, 8 Br-cAMP, which activates protein kinase A has been shown not only to result in restoration of GTPCH1 activity [26], but also attenuation of eNOS dysfunction [31,32]. Importantly, Hashimoto et al [43] reported the activation of eNOS by cilostazol via a cAMP/PKA and PI3K/Akt dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

View full text Add to dashboard Cite

C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). In this study, we examined the mechanisms by which CRP decreases eNOS activity in HAECs. To this end, we explored different strategies such as availability of tetrahydrobiopterin (BH4) -a critical cofactor for eNOS, superoxide (O 2 -) production resulting in uncoupling of eNOS and phosphorylation/dephosphorylation of eNOS. CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. Pretreatment with sepiapterin, a BH4 precursor, prevented CRP-mediated effects on BH 4 levels, superoxide production as well as eNOS activity. The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH 4 , was significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP mediated pathway. In the present study, CRP mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. Furthermore, CRP-induced O 2 -production was reversed by pharmacologic inhibition and siRNAs to p47 phox and p22 phox. Additionally, CRP treatment significantly decreased the eNOS dimer:monomer ratio confirming CRP-mediated eNOS uncoupling. The pretreatment of cells with NO synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]) also prevented CRP-mediated O 2 -production further strengthening CRP-mediated eNOS uncoupling. Additionally, CRP decreased eNOS phosphorylation at Ser1177 as well as increased phosphorylation at Thr495. CRP appears to mediate these effects through the Fcγ receptors, CD32 and CD64.To conclude, CRP uncouples eNOS resulting in increased superoxide production, decreased NO production, altered eNOS phosphorylation.

show abstract

Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

View full text Add to dashboard Cite

show abstract

“…A recent study in streptozotocin-induced diabetic rats could show a decreased renal eNOS protein production 4 weeks after diabetes induction [15]. In addition, reduced eNOS mRNA was found to be present in aortic and myocardial tissues from diabetic rats [13]. There is growing evidence for an emerging role of NO derived from eNOS in vascular defence against cardiovascular diseases [5].…”

Section: Discussionmentioning

confidence: 98%

“…While low eNOS levels have been found in diabetic aortic, renal and heart tissues [13][14][15], it remains yet unknown whether or not the NO-cGMP signalling axis can be reconstituted by an enhancement of eNOS production under these conditions. In the present study we investigated the hypothesis that pharmacological enhancement of eNOS production with AVE3085, a novel eNOS enhancer, is sufficient to activate the NO-cGMP axis, attenuate inflammatory response, and improve peripheral endothelial function in a rat model of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis Reduced bioavailability of nitric oxide (NO) is a hallmark of diabetes mellitus-induced vascular complications. In the present study we investigated whether a pharmacological increase of endothelial NO synthase (eNOS) production can restore the impaired hindlimb flow in a rat model of severe diabetes. Methods A model of diabetes mellitus was induced in male Sprague-Dawley rats by a single injection of streptozotozin. Rats were treated chronically with the eNOS transcription enhancer AVE3085 (10 mg [kg body weight] −1 day −1 ; p.o.) or vehicle for 48 days and compared with controls. Endothelial function and arterial BP were investigated in vivo using an autoperfused hindlimb model and TIPcatheter measurement, respectively. Protein production of eNOS, total and phosphorylated vasodilator-stimulated phosphoprotein (VASP) were assessed in their quadriceps muscle tissue, whereas cyclic GMP (cGMP) concentrations were assessed in blood plasma. RNA levels of intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) were measured by real-time PCR. Results Untreated diabetic rats showed significantly reduced quadriceps muscle contents of eNOS (−64%) and phosphorylated VASP (−26%) protein associated with impaired vascular function (maximum vasodilatation: −30%, p<0.05) and enhanced production of ICAM-1 (+121%) and VCAM-1 (+156%). Chronic treatment with AVE3085 did not alter arterial BP or severe hyperglycaemia, but did lead to significantly increased production of eNOS (+95%), cGMP (+128%) and VASP phosphorylation (+65%) as well as to improved vascular function (+36%) associated with reduced production of ICAM-1 (−36%) and VCAM-1 (−58%). Conclusions/interpretation In a rat model of severe diabetes, pharmacological enhancement of impaired eNOS production and NO-cGMP signalling by AVE3085 restores altered hindlimb blood flow and prevents vascular inflammation.

show abstract

“…158) Our laboratory has reported that 8-Br-cAMP, an activator of PKA markedly prevented the dysfunction of vascular endothelium. 159,160) …”

Section: Future Directionsmentioning

confidence: 99%

Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions

Balakumar¹,

Koladiya

Ramasamy

et al. 2008

JOURNAL OF HEALTH SCIENCE

Self Cite

View full text Add to dashboard Cite

Endothelium forms an innermost lining of blood vessel and it regulates the vascular tone and permeability. A healthy vascular endothelium is antiatherogenic in nature because of its properties such as inhibition of platelet aggregation, adhesion cascades, smooth muscle cell proliferation and leukocyte adhesion. Vascular endothelial dysfunction (VED) is associated with reduced synthesis and release of nitric oxide, proinflammatory and prothrombotic properties followed by diminished vasodilation. VED has been implicated in the pathogenesis of artherosclerosis, hypertension, myocardial infarction, heart failure, renal failure and stroke. Various pharmacological interventions such as angiotensin converting enzyme (ACE) inhibitors, statins, insulin sensitizers, L-arginine as well as agents that target endothelial nitric oxide synthase (eNOS) "coupling" such as folates or tetrahydrobiopterin (BH4) have been noted to improve the function of vascular endothelium. In this review, we discussed various recently developed pharmacological interventions to improve the function of endothelium. Moreover, the novel targets sites involved in the pathogenesis of vascular endothelial dysfunction have been delineated.

show abstract

Possible role of exogenous cAMP to improve vascular endothelial dysfunction in hypertensive rats

Cited by 11 publications

References 59 publications

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions

Contact Info

Product

Resources

About