Exogenous and Endogenous Adenosine Inhibits Fetal Calf Serum–Induced Growth of Rat Cardiac Fibroblasts

Dubey, Raghvendra K.; Gillespie, Delbert G.; Mi, Zaichuan; Jackson, Edwin K.

doi:10.1161/01.cir.96.8.2656

Cited by 128 publications

(139 citation statements)

References 24 publications

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“…However, the beneficial effects of ␤AR blockade are likely dominated by improvements in cardiac contractility (which would lead to decreased levels of renin-angiotensin and possibly other hormones) and myocyte survival, which in turn influence ECM formation and turnover as well as fibroblast proliferation. Our findings are consistent with data on certain other G s -linked agonist action on cardiac fibroblasts (31,39) and with a previous report that the ␤AR antagonist, propranolol, inhibits collagen deposition in pulmonary fibroblasts, cells not subjected to the mechanical forces of a contractile organ (40). In addition, our studies examine fibroblasts over a short period (24 h) and in isolation, removed from circulating catecholamines and the mechanical forces of cardiac contraction.…”

Section: Discussionsupporting

confidence: 93%

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Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Ostrom¹,

Naugle

Hase³

et al. 2003

Journal of Biological Chemistry

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Cardiac fibroblasts regulate formation of extracellular matrix in the heart, playing key roles in cardiac remodeling and hypertrophy. In this study, we sought to characterize cross-talk between G q and G s signaling pathways and its impact on modulating collagen synthesis by cardiac fibroblasts. Angiotensin II (ANG II) activates cell proliferation and collagen synthesis but also potentiates cyclic AMP (cAMP) production stimulated by ␤-adrenergic receptors (␤-AR). The potentiation of ␤-AR-stimulated cAMP production by ANG II is reduced by phospholipase C inhibition and enhanced by overexpression of G q . Ionomycin and thapsigargin increased intracellular Ca 2؉ levels and potentiated isoproterenoland forskolin-stimulated cAMP production, whereas chelation of Ca 2؉ with 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid/AM inhibited such potentiation. Inhibitors of tyrosine kinases, protein kinase C, or G␤␥ did not alter this cross-talk. Immunoblot analyses showed prominent expression of adenylyl cyclase 3 (AC3), a Ca 2؉ -activated isoform, along with AC2, AC4, AC5, AC6, and AC7. Of those isoforms, only AC3 and AC5/6 proteins were detected in caveolin-rich fractions. Overexpression of AC6 increased ␤AR-stimulated cAMP accumulation but did not alter the size of the ANG II potentiation, suggesting that the cross-talk is AC isoform-specific. Isoproterenol-mediated inhibition of serum-stimulated collagen synthesis increased from 31 to 48% in the presence of ANG II, indicating that ␤AR-regulated collagen synthesis increased in the presence of ANG II. These data indicate that ANG II potentiates cAMP formation via Ca 2؉ -dependent activation of AC activity, which in turn attenuates collagen synthesis and demonstrates one functional consequence of crosstalk between G q and G s signaling pathways in cardiac fibroblasts.

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Section: Discussionsupporting

confidence: 93%

“…Increased cellular cAMP levels can inhibit cardiac fibroblast-mediated production of collagen (31). Thus, we tested whether simultaneous incubation with cAMPelevating agents and ANG II would inhibit collagen synthesis to a greater extent than incubation with cAMP-elevating agents alone.…”

Section: Ca 2ϩmentioning

confidence: 99%

Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Ostrom¹,

Naugle

Hase³

et al. 2003

Journal of Biological Chemistry

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“…Moreover, we recently showed that vascular SMCs and cardiac fibroblasts also synthesize adenosine 17,18 and that SMC-derived as well as cardiac fibroblastderived adenosine inhibits serum-induced SMC and cardiac fibroblast growth. 17,18 Thus, if the vascular levels of adenosine are decreased in hypertension, this could contribute importantly to vascular sequelae.The first aim of the present study was to determine whether basal extracellular levels of adenosine are decreased in aortic …”

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confidence: 99%

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Dubey¹,

Mi²,

Gillespie³

et al. 2001

ATVB

Self Cite

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Abstract-The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs. Key Words: adenosine deaminase Ⅲ adenosine kinase Ⅲ hypertension Ⅲ proliferation Ⅲ vascular disease S mooth muscle cells (SMCs) within conduit and resistance arteries are importantly involved in the pathophysiology of vascular remodeling induced by hypertension. 1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR). SMC growth is regulated by multiple factors. 1 Under normal conditions, vascular SMC quiescence is maintained by a balance between vessel wall-derived and circulating growth inhibitors and growth promoters. 1 Disruption of the balanced generation of growth promoters and growth inhibitors under pathological conditions triggers a cascade of events leading to increased proliferation of SMCs and enhanced deposition of extracellular matrix proteins by SMCs. Therefore, endogenous factors that are generated by cells within the vessel wall and that inhibit SMC growth may play a major vasoprotective role, and decreased vascular levels of growth-inhibitory factors may contribute to vascular disease in hypertension.In this regard, it is conceivable that dysregulation of vascular adenosine levels in hyp...

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“…The components dynamically change, increase, decrease, or reorganize, in response to physiological and pathological stimuli (Dubey et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Remodeling of Autologous Artery Graft Interposed to Vein in Rabbit

Feng

Shen

Zhang

2011

The Anatomical Record

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Our previous study found that the artery interposed to vein did not develop atherosclerosis but rather underwent atrophic remodeling in hyperlipidemic rabbits, suggesting that local hemodynamic load was another important determinant for the development of atherosclerosis. This study focused on the cellular and molecular changes in autologous artery grafts derived from rabbits fed with high lipid diet for 1, 2, 4, 8, and 12 weeks. Thickness, area of vessel wall, and lumen area were measured and analyzed on the grafted common carotid artery (GCCA) interposed to vein and on the right common carotid artery. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling. Both elastin and collagen of GCCA were identified by the method of double stains of elastin and collagen. Reverse transcription polymerase chain reaction was used to observe matrix metalloproteinases (MMPs) mRNA expression changes in the examined arteries. The lumen area increased gradually in control common carotid artery and remained unchanged in GCCA 3 months later, since the surgery and the start of high lipid diet, while significantly increased apoptosis was evidenced from inner to outer part of GCCA. Collagen content decreased gradually and elastic fibers remained unchanged in GCCA. At 1 week after operation, the mRNA expression of MMP 2 and MMP 9 increased significantly and returned to baseline thereafter. The artery interposed to a vein underwent atrophy, characterized by increased apoptosis in the vessel wall from intima to adventitia, possibly due to low shear stress circumference and reduced vessel collagen resulting from postsurgical upregulated MMP 2 and MMP 9 expression. Anat Rec,

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Exogenous and Endogenous Adenosine Inhibits Fetal Calf Serum–Induced Growth of Rat Cardiac Fibroblasts

Cited by 128 publications

References 24 publications

Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Molecular Mechanism of Remodeling of Autologous Artery Graft Interposed to Vein in Rabbit

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