Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels

Manning, Janet R.; Carpenter, Gregory; Porter, Darius; House, Stacey L.; Pietras, Daniel; Doetschman, Thomas; Schultz, Jo El J.

doi:10.3109/08977194.2012.656759

Cited by 10 publications

(5 citation statements)

References 93 publications

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“…42,43 Here, we show that ticagrelor, but not clopidogrel, attenuates the increase in MIP-2 4 weeks after myocardial infarction. 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.…”

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

107

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

107

111

View full text Add to dashboard Cite

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“…L5-LDL isolated from these patients has demonstrated the ability to induce endothelial dysfunction and injury. In cultured vascular endothelial cells, L5-LDL induces apoptosis by inhibiting the expression of fibroblast growth factor-2 (FGF2) (8,10,49), a pleiotropic protein that maintains a normal endothelial physiology and protects against myocardial infarction (11,27,28). L5-LDL also mediates inflammatory effects in vascular cells during the progression of atherosclerosis (17).…”

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confidence: 99%

L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages

Yang

Chang

2017

American Journal of Physiology-Heart and Circulatory Physiology

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This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1β in macrophages. The results showed that L5-LDL induced activation of caspase-1 and NF-κB through the lectin-type oxidized LDL receptor (LOX-1)-dependent pathway, leading to the production of IL-1β.

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“…bFGF is an important molecule that has demonstrated its usefulness in terms of regenerative medicine in a broad range of applications. 29,30 As with previous proteins that demonstrated enhanced bioactivity after multivalent conjugation, 26,27 oligomerization of bFGF is an endogenous mechanism to modulate its function in vivo . 31 Dimerization is key to bFGF activity, as it leads to FGFR dimerization and activation.…”

Section: Introductionmentioning

confidence: 77%

Multivalent conjugates of basic fibroblast growth factor enhance in vitro proliferation and migration of endothelial cells

et al. 2018

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Growth factors hold great promise for regenerative therapies. However, their clinical use has been halted by poor efficacy and rapid clearance from tissue, necessitating the delivery of extremely high doses to achieve clinical effectiveness which has raised safety concerns. Thus, strategies to either enhance growth factor activity at low doses or to increase their residence time within target tissues are necessary for clinical success. In this study, we generated multivalent conjugates (MVCs) of basic fibroblast growth factor (bFGF), a key growth factor involved in angiogenesis and wound healing, to hyaluronic acid (HyA) polymer chains. Multivalent bFGF conjugates (mvbFGF) were fabricated with minimal non-specific interaction observed between bFGF and the HyA chain. The hydrodynamic radii of mvbFGF ranged from ∼50 to ∼75 nm for conjugation ratios of bFGF to HyA chains at low (10 : 1) and high (30 : 1) feed ratios, respectively. The mvbFGF demonstrated enhanced bioactivity compared to unconjugated bFGF in assays of cell proliferation and migration, processes critical to angiogenesis and tissue regeneration. The 30 : 1 mvbFGF outperformed the 10 : 1 conjugate, which could be due to either FGF receptor clustering or interference with receptor mediated internalization and signal deactivation. This study simultaneously investigated the role of both protein to polymer ratio and multivalent conjugate size on their bioactivity, and determined that increasing the protein-to-polymer ratio and conjugate size resulted in greater cell bioactivity.

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Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels

Cited by 10 publications

References 93 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

L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages

Multivalent conjugates of basic fibroblast growth factor enhance in vitro proliferation and migration of endothelial cells

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