Fibroblast Growth Factor-2 Regulates Myocardial Infarct Repair

Virag, Jitka A. I.; Rolle, Marsha W.; Reece, Julia C.; Hardouin, S; Feigl, Eric O.; Murry, Charles E.

doi:10.2353/ajpath.2007.070003

Cited by 154 publications

(60 citation statements)

References 42 publications

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“…However, FGF-2 induces cardioprotection, 44 has a role as a chemotactic factor for stem cell homing after myocardial injury, 45 induces angiogenesis, 46,47 and improves remodeling after myocardial infarction in the rat. [48][49][50] The significance of the ticagrelorinduced attenuation and clopidogrel-induced normalization of the increase in FGF-2 levels 4 weeks after infarction is unclear. Although ticagrelor attenuated adverse remodeling after infarction, clopidogrel had no effect.…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Ye¹,

Birnbaum

Perez‐Polo

et al. 2015

ATVB

108

111

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Objective-In addition to P2Y 12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. Approach and Results-Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks.(1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/ kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%).All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A 4 levels. Conclusions-Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect. addition to platelet inhibition, ticagrelor, but not clopidogrel, has protective effects against ischemia-reperfusion that may help explain the differences in clinical benefit in the PLATO trial. 7,8 However, a recent multicenter, randomized, double-blind clinical trial did not show a clear clinical benefit in patients with STEMI receiving ticagrelor en route to the hospital versus in the catheterization laboratory. 16 As the study was not powered for benefit on cardiovascular events, it is inconclusive about the hypothesis that administration of ticagrelor after onset of ischemia (in contrast to pretreatment just before reperfusion) can ameliorate reperfusion injury. In addition, as the median time difference between the prehospital and the in-hospital ticagrelor administration groups was only 31 minutes, 16 it is plausible that ticagrelor absorption was insufficient an...

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Section: Discussionmentioning

confidence: 99%

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Ye¹,

Birnbaum

Perez‐Polo

et al. 2015

ATVB

108

111

View full text Add to dashboard Cite

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“…Fast Green/Picrosirius Red stains collagen red and counterstains other tissue components green to allow visualization of interstitial collagen. 20 Microscopic images were acquired with a digital camera (Leica DFC 480) on an upright microscope (Leica DMLB2).…”

Section: Methodsmentioning

confidence: 99%

Self‐assembled smooth muscle cell tissue rings exhibit greater tensile strength than cell‐seeded fibrin or collagen gel rings

Adebayo

Hookway

et al. 2012

J Biomedical Materials Res

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In this study, we created self-assembled smooth muscle cell (SMC) tissue rings (comprised entirely of cells and cell-derived matrix; CDM) and compared their structure and material properties with tissue rings created from SMC-seeded fibrin or collagen gels. All tissue rings were cultured statically for 7 days in supplemented growth medium (with ε-amino caproic acid, ascorbic acid, and insulin-transferrin-selenium), prior to uniaxial tensile testing and histology. Self-assembled CDM rings exhibited ultimate tensile strength and stiffness values that were two-fold higher than fibrin gel and collagen gel rings. Tensile testing of CDM, fibrin gel and collagen gel rings treated with deionized water to lyse cells showed little to no change in mechanical properties relative to untreated ring samples, indicating that the ECM dominates the measured ring mechanics. In addition, CDM rings cultured in supplemented growth medium were significantly stronger than CDM rings cultured in standard, unsupplemented growth medium. These results illustrate the potential utility of self-assembled cell rings as model CDM constructs for tissue engineering and biomechanical analysis of ECM material properties.

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“…Indeed, it has been shown that compared to wild-type mice, FGF2 deficient mice develop less fibrosis when challenged by coronary ligation (88). Furthermore in response to AngII, cardiac fibroblasts release FGF2 that in an autocrine manner induces fibroblast activation and in a paracrine manner causes hypertrophic growth of cardiac myocytes (70).…”

Section: The Effects Of Paracrine Fibroblast Growth Factors On the Heartmentioning

confidence: 99%

Cardiac actions of fibroblast growth factor 23

Faul

2017

Bone

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Fibroblast growth factors (FGF) are mitogenic signal mediators that induce cell proliferation and survival. Although cardiac myocytes are post-mitotic, they have been shown to be able to respond to local and circulating FGFs. While precise molecular mechanisms are not well characterized, some FGF family members have been shown to induce cardiac remodeling under physiologic conditions by mediating hypertrophic growth in cardiac myocytes and by promoting angiogenesis, both events leading to increased cardiac function and output. This FGF-mediated physiologic scenario might transition into a pathologic situation involving cardiac cell death, fibrosis and inflammation, and eventually cardiac dysfunction and heart failure. As discussed here, cardiac actions of FGFs - with the majority of studies focusing on FGF2, FGF21 and FGF23 - and their specific FGF receptors (FGFR) and precise target cell types within the heart, are currently under experimental investigation. Especially cardiac effects of endocrine FGFs entered center stage over the past five years, as they might provide communication routes that couple metabolic mechanisms, such as bone-regulated phosphate homeostasis, or metabolic stress, such as hyperphosphatemia associated with kidney injury, with changes in cardiac structure and function. In this context, it has been shown that elevated serum FGF23 can directly tackle cardiac myocytes via FGFR4 thereby contributing to cardiac hypertrophy in models of chronic kidney disease, also called uremic cardiomyopathy. Precise characterization of FGFs and their origin and regulation of expression, and even more importantly, the identification of the FGFR isoforms that mediate their cardiac actions should help to develop novel pharmacological interventions for heart failure, such as FGFR4 inhibition to tackle uremic cardiomyopathy.

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Fibroblast Growth Factor-2 Regulates Myocardial Infarct Repair

Cited by 154 publications

References 42 publications

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Self‐assembled smooth muscle cell tissue rings exhibit greater tensile strength than cell‐seeded fibrin or collagen gel rings

Cardiac actions of fibroblast growth factor 23

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