Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration

Yamahara, Kenichi; Itoh, Hiroshi; Chun, Tae Hwa; Ogawa, Yoshihiro; Yamashita, Jun; Sawada, Naoki; Fukunaga, Yasutomo; Sone, Masakatsu; Yurugi-Kobayashi, Takami; Miyashita, Kazutoshi; Tsujimoto, Hirokazu; Kook, Hyun; Feil, Robert; Garbers, David L.; Hofmann, Franz; Nakao, Kazuwa

doi:10.1073/pnas.0538059100

Cited by 153 publications

(141 citation statements)

References 35 publications

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“…a variety of vasculoproliferative processes under pathological conditions. This view is supported by the recent finding that ischemia-induced angiogenesis is impaired in cGKI-deficient mice (28). Others reported that cGMP and cGKI inhibit SMC proliferation in vitro (for reviews, see refs.…”

Section: Activation Of Cgki In Primary Aortic Smcs Stimulates Phenotymentioning

confidence: 76%

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

Wolfsgruber¹,

Feil²,

Brummer³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO) exerts both antiatherogenic and proatherogenic effects, but the cellular and molecular mechanisms that contribute to modulation of atherosclerosis by NO are not understood completely. The cGMP-dependent protein kinase I (cGKI) is a potential mediator of NO signaling in vascular smooth muscle cells (SMCs). Postnatal ablation of cGKI selectively in the SMCs of mice reduced atherosclerotic lesion area, demonstrating that smooth muscle cGKI promotes atherogenesis. Cell-fate mapping indicated that cGKI is involved in the development of SMC-derived plaque cells. Activation of endogenous cGKI in primary aortic SMCs resulted in cells with increased levels of proliferation; increased levels of vascular cell adhesion molecule-1, peroxisome proliferator-activated receptor ␥, and phosphatidylinositol 3-kinase͞Akt signaling; and decreased plasminogen activator inhibitor 1 mRNA, which all are potentially proatherogenic properties. Taken together, these results highlight the pathophysiologic significance of vascular SMCs in atherogenesis and identify a key role for cGKI in the development of atherogenic SMCs in vitro and in vivo. We suggest that activation of smooth muscle cGKI contributes to the proatherogenic effect of NO and that inhibition of cGKI might be a therapeutic option for treating atherosclerosis in humans.A therosclerosis causes heart attack and stroke, the major causes of death in industrial nations. The pathophysiology of atherogenesis is complex. It is considered to be a chronic inflammatory condition that results from the interaction between modified lipoproteins and various cell types, including leukocytes, platelets, and cells of the vessel wall (1). The development of an atherosclerotic plaque involves, in addition to inflammation, the phenotypic modulation of vascular smooth muscle cells (SMCs) to proliferating and dedifferentiated cells. However, the mechanisms that contribute to the development of plaque SMCs and their pathophysiologic significance are not well understood (2).The signaling molecule nitric oxide (NO) has critical roles in the pathogenesis of atherosclerosis (3). Analysis of transgenic mice that lack or overexpress NO synthases indicated that NO exerts both protective (4, 5) and atherogenic (6-9) effects. The double role of NO might explain why NO-generating drugs (e.g., glyceryl trinitrate) have not been reported to limit the progression of atherosclerosis in humans. The opposing actions of NO on atherogenesis might depend on the spatiotemporal profile of its production and are likely mediated by different cellular and molecular mechanisms. Signaling pathways in SMCs that contribute to NO modulation of atherogenesis have not been identified. In vascular SMCs, NO is thought to exert many of its effects by activation of soluble guanylyl cyclase, synthesis of the second messenger cGMP, and activation of cGMP-dependent protein kinase I (cGKI) (10). The analysis of the functional significance of cGKI in NO͞cGMP signaling is complicated by the existence of multiple receptors ...

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Section: Activation Of Cgki In Primary Aortic Smcs Stimulates Phenotymentioning

confidence: 76%

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

Wolfsgruber¹,

Feil²,

Brummer³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, we wished to obtain insight into which NPR was involved in mediating CNP-induced inhibition of leukocyte rolling. In this regard, we used the selective NPR-C agonist (17), cANF [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] (because of the lack of availability of selective NPR-B antagonists). cANF [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] mimicked the inhibitory actions of CNP on leukocyte recruitment; although this observation only provides circumstantial evidence that CNP exerts its antileukocyte effects via this NPR, it does demonstrate that NPR-C activation is functionally important in the regulation of leukocyte-endothelial cell interactions.…”

Section: Discussionmentioning

confidence: 99%

“…CNP (0.1-1 M) was superfused for 10 min, and leukocyte flux was recorded. To investigate the involvement of the NPR-C in responses to CNP, the ability of the selective NPR-C agonist (17), cANF [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] (1 M) to inhibit leukocyte rolling was also explored.…”

Section: Assessment Of the Effect Of Cnp On Basal Leukocyte Activatiomentioning

confidence: 99%

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C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

Scotland

Cohen

Foster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The multifaceted process of immune cell recruitment to sites of tissue injury is key to the development of an inflammatory response and involved in the pathogenesis of numerous cardiovascular disorders. We recently identified C-type natriuretic peptide (CNP) as an important endothelium-derived mediator that regulates vascular tone and protects against myocardial ischemia͞ reperfusion injury. Herein, we investigated whether CNP inhibits leukocyte recruitment and platelet aggregation and thereby exerts a potential antiinflammatory influence on the blood vessel wall. We assessed the effects of CNP on leukocyte-endothelial cell interactions in mouse mesenteric postcapillary venules in vivo in animals with high basal leukocyte activation (endothelial nitric oxide synthase knockout mice, eNOS ؊/؊ ) or under acute inflammatory conditions (induced by interleukin-1␤ or histamine). CNP suppressed basal leukocyte rolling in eNOS ؊/؊ mice in a rapid, reversible, and concentration-dependent manner. These effects of CNP were mimicked by the selective natriuretic peptide receptor-C agonist cANF 4 -23 . CNP also suppressed leukocyte rolling induced by IL-1␤ or histamine, inhibited platelet-leukocyte interactions, and prevented thrombin-induced platelet aggregation of human blood. Furthermore, analysis of human umbilical vein endothelial cells, leukocytes, and platelets revealed that CNP selectively attenuates expression of P-selectin. Thus, CNP is a modulator of acute inflammation in the blood vessel wall characterized by leukocyte and platelet activation. These antiinflammatory effects appear to be mediated, at least in part, via suppression of P-selectin expression. These observations suggest that endothelial CNP might maintain an anti-atherogenic influence on the blood vessel wall and represent a target for therapeutic intervention in inflammatory cardiovascular disorders.endothelium ͉ natriuretic peptide receptor type C ͉ atherosclerosis ͉ thrombosis L eukocyte recruitment and platelet activation at sites of tissue injury are important facets of an inflammatory response and are pivotal in the pathogenesis of a number of cardiovascular disorders including atherosclerosis and sepsis. These processes are triggered by specific inflammatory stimuli and are critically dependent on the expression of a series of adhesion molecules on the surface of leukocytes, platelets, and the vascular endothelium (1). However, this is a dynamic process; under basal (physiological) conditions, leukocyte and platelet activation is held in check by specific endothelium-derived mediators. Perhaps the most influential of these is nitric oxide (NO), which, in concert with analogous autacoids such as prostacyclin, maintains an active suppression of leukocyte and platelet activation under physiological conditions that is paramount for maintenance of blood vessel integrity and patency (2-4).The importance of NO in the prevention of leukocyte recruitment has been established by studies demonstrating increased leukocyte-endothelial interactions in animals ...

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“…Twenty different random microscopic fields on five different sections from each animal were photographed and analyzed by MetaMorph software. Capillary density was expressed as number of capillaries per high power field (ϫ400) as described previously (27,28).…”

Section: Generation Of Ec-selective Mir-15a Transgenic (Ec-mir-15a Tg)mentioning

confidence: 99%

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

Yin

Olsen

Hamblin

et al. 2012

Journal of Biological Chemistry

126

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Background: MicroRNAs mediate angiogenesis in both physiological and pathological conditions, but underlying molecular mechanisms are largely unexplored. Results: Endothelial miR-15a negatively regulates angiogenesis in vivo and in vitro by suppression of FGF2 and VEGF. Conclusion: MiR-15a inhibits endothelial autonomous angiogenesis. Significance: MiR-15a is a negative regulator of angiogenesis and a potential target for the restorative therapy of ischemic diseases.

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Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration

Cited by 153 publications

References 35 publications

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells

C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

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