Fibroblast Growth Factor-2 Mediates Angiotensin-Converting Enzyme Inhibitor-Induced Angiogenesis in Coronary Endothelium

Donnini, Sandra; Solito, Raffaella; Giachetti, Antonio; Granger, Harris J.; Ziche, Marina; Morbidelli, Lucia

doi:10.1124/jpet.106.108803

Cited by 34 publications

(39 citation statements)

References 39 publications

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“…For example, ACE inhibitor treatment improves endothelial function in septic patients (71) or in rabbits with lipopolysaccharide-induced endotoxic shock by an NO-dependent mechanism (72). ACE inhibitors also promote angiogenesis in an NO-dependent manner that results from B1R activation (73).…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Zhang

Tan

Zhang

et al. 2008

Journal of Biological Chemistry

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Kinin B1 receptor (B1R) expression is induced by injury or inflammatory mediators, and its signaling produces both beneficial and deleterious effects. Kinins cleaved from kininogen are agonists of the B2R and must be processed by a carboxypeptidase to generate B1R agonists des-Arg 9 -bradykinin or desArg 10 Carboxypeptidase M (CPM) 2 was discovered as a glycosylphosphatidylinositol (GPI)-anchored membrane protein with B-type carboxypeptidase activity (1-3) and is a member of the "regulatory" or carboxypeptidase N/E subfamily of metallocarboxypeptidases (4 -8) based on its cDNA sequence (9), genomic structure (10), and x-ray crystal structure (11). The overall structure of CPM is composed of a 295-residue N-terminal catalytic domain, followed by an 86-residue conical ␤-sandwich (transthyretin-like domain) and a unique 25-residue extension to which the GPI anchor is post-translationally attached (11).CPM cleaves only C-terminal Arg or Lys residues, and some of its endogenous substrates include bradykinin, anaphylatoxins C3a, C4a, and C5a, Arg-or Lys-enkephalins, epidermal growth factor, and hemoglobin (2, 7, 12, 13). CPM preferentially cleaves C-terminal Arg as exemplified by the kinetics with Arg 6 -Met 5 -enkephalin (K m ϭ 46 M, k cat ϭ 934 min Ϫ1 ) versus Lys 6 -Met 5 -enkephalin (K m ϭ 375 M, k cat ϭ 663 min Ϫ1 ) (2). Bradykinin exhibits the lowest K m (16 M) of any CPM substrate tested (2), a concentration that is still much higher than the typical physiological concentration of this peptide in the nanomolar range. However, peptidases in vivo typically work at substrate concentrations far below the K m as exemplified by angiotensin I-converting enzyme (ACE), which has the same relatively high K m (16 M) with angiotensin I (14), a major physiological substrate. The development of ACE inhibitors as effective agents for treating hypertension and cardiovascular diseases was based in large part on the critical role of this enzyme in converting angiotensin I to II in vivo (15).The kinin peptides bradykinin and kallidin (Lys-bradykinin) are generated by the proteolytic action of plasma or tissue kallikrein on high or low molecular weight kininogen (16,17). Removal of the C-terminal Arg from bradykinin or kallidin inactivates these peptides as agonists of the constitutively expressed B2 receptor (B2R) (16,17). However, this conversion is a required processing step to generate desArg 9 -bradykinin or des-Arg 10 -kallidin (16, 18), metabolites that have a variety of biological activities mediated by specific activation of a different B1 receptor (B1R) whose expression is induced by inflammatory mediators (19,20). Thus, CPM acts as a cell surface processing enzyme to generate des-Arg-kinin agonists for the B1R, and without this catalytic conversion, B1R signaling could not occur. This is of potential importance in inflammatory or pathological responses. For example, B1R activation stimulates extracellular signal-regulated kinase phosphorylation, prostaglandin production (20), and inducible nitric-oxide synthase-mediate...

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Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Zhang

Tan

Zhang

et al. 2008

Journal of Biological Chemistry

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“…Pseudocapillary sprouting from vessel rings of the human umbilical artery and characterization of the cells present in the pseudocapillaries were evaluated as described previously (Donnini et al, 2006). Cell Cultures.…”

Section: Methodsmentioning

confidence: 99%

“…We resuspended 1000 cells per well (of a 96-well multiplate) in 10% CS, and after cell adherence (3-4 h), we replaced the supernatant with medium containing ACEI (0.01-10 M) and 0.1% CS. Cells were kept in culture for 5 consecutive days, and medium with test substances was added freshly at 36 and 72 h. Cells were then fixed, stained, and randomly counted at 10ϫ magnification (Donnini et al, 2006). Cell survival in response to ACEI was also assessed by the MTT test (Pezzatini et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

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Sulfhydryl Angiotensin-Converting Enzyme Inhibitor Promotes Endothelial Cell Survival through Nitric-Oxide Synthase, Fibroblast Growth Factor-2, and Telomerase Cross-Talk

Donnini¹,

Terzuoli²,

Ziche³

et al. 2009

J Pharmacol Exp Ther

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The protective effect exerted by angiotensin-converting enzyme inhibitors (ACEI) in cardiovascular diseases caused by endothelial injury and aging has been attributed to the restoration of endothelial cell functions. Recently, we demonstrated a central role of the fibroblast growth factor-2 (FGF-2)/FGF receptor-1 system in mediating the acquisition of an angiogenic phenotype in coronary microvascular endothelium exposed to ACEI. Here, we report on the rescuing effect of ACEI on impaired endothelium and the intracellular signaling mechanisms that lead endothelial cells to enter apoptosis and to senesce. Conditions mimicking pathological cell damage (serum deprivation) lead to endothelial apoptosis as evidenced by increased caspase-3 activity. ACEI enhanced cell survival through activation of prosurvival and antiaging signals involving Akt phosphorylation, endothelial nitricoxide synthase (eNOS) expression and activation, FGF-2 and telomerase catalytic subunit (TERT) up-regulation, and delayed senescence. In microvascular endothelial cells exposed to ACEI, Akt/eNOS pathway-dependent FGF-2 was necessary for gene transcription of TERT. These protective effects were particularly evident for sulfhydryl-containing ACEI (zofenoprilat), which were reported to exhibit potent antioxidant effects. In conclusion, ACEI with antioxidant properties up-regulate eNOS, FGF-2, and TERT mRNA, which favor endothelial cell survival and prolong their lifespan, thus restoring endothelial cell functions after vascular damage. These effects could explain the beneficial effects of these drugs in various cardiovascular diseases associated with endothelial injury and aging.Since the introduction into clinical use of angiotensinconverting enzyme inhibitors (ACEI), our understanding of their mechanism of action has evolved from the widely held tenet that the therapeutic benefit of ACEI is exclusively associated with the decrease of vascular tone consequent to the inhibition of angiotensin II formation. This initial hypothesis has been disputed because of clinical evidence indicating that, even with marginal decreases of blood vessel tone, ACEI provide significant benefits (e.g., decreased mortality) in a large number of patients suffering from cardiac heart failure, acute myocardial infarction, and diabetes complications (Yusuf et al., 2000; Boss and Dawes, 2004;Kjeldsen and Julius, 2004;Brugts et al., 2009). The common thread linking these diverse diseases is endothelium dysfunction, widely recognized as one of the factors implicated in these pathologies. Reports in the literature describe improvement of damaged endothelium attributable to ACEI as well as the effects of ACEI on promoting vascular remodeling and diminishing the burden of cardiovascular risk factors (Galderisi and de Devitiis, 2008). The underlying mechanism of the protection exhibited by ACEI has been attributed to their ability to influence the enzyme endothelial nitric-oxide synthase (eNOS), favoring the proper assembly of the enzyme complex and the engagement of it...

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“…ACE inhibitors are widely used as antihypertensive drugs. Recently, studies reported the beneficial effects of ACE inhibitors on tumor growth by inhibiting neovascularization 27,28 and in myocardial ischemia by improving angiogenesis 29 . In this study, we found that enalapril increased angiogenesis in diabetic and diabetic hind limb ischemic rats.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Angiogenesis by Enalapril in Diabetic Hindlimb Ischemc Rats

Fallahzadeh

Khazaei²,

Sharifi³

2011

BIOMED PAP

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Fibroblast Growth Factor-2 Mediates Angiotensin-Converting Enzyme Inhibitor-Induced Angiogenesis in Coronary Endothelium

Cited by 34 publications

References 39 publications

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Sulfhydryl Angiotensin-Converting Enzyme Inhibitor Promotes Endothelial Cell Survival through Nitric-Oxide Synthase, Fibroblast Growth Factor-2, and Telomerase Cross-Talk

Restoration of Angiogenesis by Enalapril in Diabetic Hindlimb Ischemc Rats

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