Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia

House, Stacey L.; Bolte, Craig; Zhou, Ming; Doetschman, Thomas; Klevitsky, Raisa; Newman, Gilbert; Schultz, Jo El J.

doi:10.1161/01.cir.0000105723.91637.1c

Cited by 115 publications

(131 citation statements)

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“…FGF signaling is important for wound healing and for limiting scar size following myocardial ischemia (29)(30)(31)(32). Despite these well-established functions for FGF signaling, its cellular sites of action in complex tissues are poorly defined.…”

Section: Impaired Neovascularization and Delayed Wound Healing In Micementioning

confidence: 99%

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Oladipupo

Smith

Santeford

et al. 2014

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

119

107

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Endothelial cells (ECs) express fibroblast growth factor receptors (FGFRs) and are exquisitely sensitive to FGF signals. However, whether the EC or another vascular cell type requires FGF signaling during development, homeostasis, and response to injury is not known. Here, we show that Flk1-Cre or Tie2-Cre mediated deletion of FGFR1 and FGFR2 (Fgfr1/2Flk1-Cre or Fgfr1/ 2 Tie2-Cre mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2 Flk1-Cre mice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2Flk1-Cre and Fgfr1/2Tie2-Cre mice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsufficiency. Also, impaired neovascularization was associated with delayed cutaneous wound healing. These findings reveal a key requirement for cell-autonomous EC FGFR signaling in injuryinduced angiogenesis, but not for vascular homeostasis, identifying the EC FGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.choroidal neovascularization | oxygen-induced retinopathy | retinopathy of prematurity | neoangiogenesis N eovascularization is critical for tissue repair and pathological conditions, including aberrant ocular angiogenesis and cancer (1-4). Although FGF signaling has been prominently implicated in these processes based on genetic inactivation experiments in mice and in vitro studies, the functional in vivo requirement of this pathway in the endothelial cell (EC) vs. other vascular cell types is not known (5-8).The FGF family is composed of 18 signaling ligands, which interact with four cell surface tyrosine kinase receptors. FGF receptor (FGFR) signaling regulates many biological processes, including survival, differentiation, proliferation, and angiogenesis through the activation of RAS-RAF-MAPK, PI3K, STAT, and PLC gamma pathways (6, 9). The EC response to FGF signals is well described in in vitro models of angiogenesis (10, 11). Moreover, previous gene expression analysis showed that Fgfr1 and Fgfr2 were the predominant Fgfrs in ECs (5), whereas Fgfr3 was sparsely detected (12, 13) and Fgfr4 expression was not reported (8). To this end, and given the critical role of FGFRs 1 and 2 during embryonic development, we tested the hypothesis that EC FGFR1/2 may play a key role during vascular development, homeostasis, and response to injury.Studies aimed at understanding the functional requirement of vascular FGF signaling have demonstrated a critical role in homeostasis and angiogenesis (14-16). In these studies, in vivo expression of an adenoviral-based soluble FGF trap (sFGFR) or a dominant inhibitor of all FGFRs (FGF...

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Section: Impaired Neovascularization and Delayed Wound Healing In Micementioning

confidence: 99%

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Oladipupo

Smith

Santeford

et al. 2014

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

119

107

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“…Hearts were rapidly excised, the aorta and pulmonary vein were rapidly cannulated to induce a working-heart system with a cardiac output of 5 ml/min and a constant afterload of 50 mmHg, and establishment of baseline cardiac and hemodynamic parameters of cardiac output, aortic pressure, aortic and coronary flow, left ventricular systolic and diastolic pressure, and contractility (ϩdP/dt, positive derivative of the left ventricular pressure with respect to time), and relaxation (ϪdP/dt, negative derivative of the left ventricular pressure with respect to time) occurred. Mouse hearts were subjected to global low-flow I/R injury as previously described (26). Ischemia was induced by reducing total cardiac output from 5 to 1 ml/min for 1 h resulting in a Ͼ90% reduction in coronary flow, after which the heart was reperfused at 5 ml/min for 2 h. icity colorimetric assay per the manufacturers' instructions and normalized to heart weight and coronary flow.…”

Section: I/r Injurymentioning

confidence: 99%

“…Snap-frozen nonischemic hearts were powdered and homogenized in homogenization buffer (20 mM Tris, 2 mM EDTA, 2 M NaCl, 1% NP40, and PMSF), and FGF2 was extracted as previously described (26). Western blot analysis of the extracted FGF2 was performed with a rabbit polyclonal antibody to FGF2 (1:1,000; Santa Cruz Biotechnology).…”

Section: Cardiac Preparation and Immunoblotting For Detection Of Fgf2mentioning

confidence: 99%

“…There is a profound and immediate need to address the problem of myocardial dysfunction and infarction associated with cardiac ischemia and reperfusion (I/R). One promising therapeutic strategy to alleviate I/R-induced cardiac injury is fibroblast growth factor-2 (FGF2).FGF2, found at elevated levels in the serum of I/R patients (63), has both angiogenic and acute cardioprotective effects (6,26,37,54,64). This makes FGF2 an outstanding candidate for the treatment of cardiac patients; however, while in recent years, there have been a number of noteworthy developments characterizing the mechanism of action of FGF2 in the ischemic heart, there are several unanswered questions that must be addressed before FGF2 becomes a therapeutic molecule.…”

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confidence: 99%

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Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction

Manning

Perkins

Sinclair

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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JJ. Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction. Am J Physiol Heart Circ Physiol 304: H1382-H1396, 2013. First published March 11, 2013 doi:10.1152/ajpheart.00613.2012.-Among its many biological roles, fibroblast growth factor-2 (FGF2) acutely protects the heart from dysfunction associated with ischemia/reperfusion (I/R) injury. Our laboratory has demonstrated that this is due to the activity of the low molecular weight (LMW) isoform of FGF2 and that FGF2-mediated cardioprotection relies on the activity of protein kinase C (PKC); however, which PKC isoforms are responsible for LMW FGF2-mediated cardioprotection, and their downstream targets, remain to be elucidated. To identify the PKC pathway(s) that contributes to postischemic cardiac recovery by LMW FGF2, mouse hearts expressing only LMW FGF2 (HMWKO) were bred to mouse hearts not expressing PKC␣ (PKC␣KO) or subjected to a selective PKCε inhibitor (εV1-2) before and during I/R. Hearts only expressing LMW FGF2 showed significantly improved postischemic recovery of cardiac function following I/R (P Ͻ 0.05), which was significantly abrogated in the absence of PKC␣ (P Ͻ 0.05) or presence of PKCε inhibition (P Ͻ 0.05). Hearts only expressing LMW FGF2 demonstrated differences in actomyosin ATPase activity as well as increases in the phosphorylation of troponin I and T during I/R compared with wild-type hearts; several of these effects were dependent on PKC␣ activity. This evidence indicates that both PKC␣ and PKCε play a role in LMW FGF2-mediated protection from cardiac dysfunction and that PKC␣ signaling to the contractile apparatus is a key step in the mechanism of LMW FGF2-mediated protection against myocardial dysfunction. low molecular weight FGF2; PKC␣ and ε; troponin; actomyosin ATPase; postischemic cardiac function CARDIOVASCULAR DISEASE IS the number one killer in the U.S., and every year over eight million people in the U.S. suffer from myocardial infarction (43). Often, myocardial ischemia is characterized by lowered postischemic left ventricular function, which is associated with increased morbidity and mortality (7). There is a profound and immediate need to address the problem of myocardial dysfunction and infarction associated with cardiac ischemia and reperfusion (I/R). One promising therapeutic strategy to alleviate I/R-induced cardiac injury is fibroblast growth factor-2 (FGF2).FGF2, found at elevated levels in the serum of I/R patients (63), has both angiogenic and acute cardioprotective effects (6,26,37,54,64). This makes FGF2 an outstanding candidate for the treatment of cardiac patients; however, while in recent years, there have been a number of noteworthy developments characterizing the mechanism of action of FGF2 in the ischemic heart, there are several unanswered questions that must be addressed before FGF2 becomes a therapeutic molecule. Yet to be determined is the distinct role each FGF2 isoform plays in the ischemic heart. FGF2...

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“…Over the past 10 years, it has been realized that expression of a number of known proangiogenic factors can promote coronary vessel growth in animal models. Overexpression of fibroblast growth factor-2 (FGF2), vascular endothelial growth factor-A (VEGF-A), and angiopoietin-2 (ANG2) in the myocardium of adult mice leads to significant increases in coronary artery number (House et al 2003, Landau et al 1995, Rajanayagam et al 2000, Syed et al 2004, Tammela et al 2005, Uchida et al 1995, Visconti et al 2002. Since these initial observations, the effects of Fgf2 and Vegf-A in the adult heart have been intensively investigated and proposed as candidates for the treatment of ischemic heart disease (Scheinowitz et al 1997, Syed et al 2004.…”

Section: Ischemic Heart Diseasementioning

confidence: 99%

Rebuilding the Coronary Vasculature: Hedgehog as a New Candidate for Pharmacologic Revascularization

Lavine

Ornitz

2007

Trends in Cardiovascular Medicine

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Myocardial infarction and ischemic heart disease are among the most common causes of morbidity and mortality in the industrial world. Surgical and percutaneous intravascular approaches are commonly used to treat these diseases. Regrettably, a significant number of patients are either ineligible or demonstrate suboptimal responses to these therapies. In an attempt to provide such patients improved therapeutic options, much effort has been spent developing noninvasive approaches to restore coronary vascular perfusion. One such strategy, termed therapeutic revascularization or angiogenesis, involves administration of proangiogenic factors, which improve coronary perfusion by promoting growth of the coronary vasculature. Thus far, two potential proangiogenic factors have been intensively examined, fibroblast growth factor and vascular endothelial growth factor. Unfortunately, despite their apparent efficacy in animal models, neither factor has performed adequately in the clinic to date. Within the past year a new factor, hedgehog, has been shown to effectively promote the growth of the coronary vasculature and thus has been proposed as a novel candidate for therapeutic revascularization. In this review, we discuss the discovery of the hedgehog pathway as an essential regulator of the development of the coronary vasculature, as an inducer of adult coronary vascular growth, and as a therapeutic in the treatment of ischemic heart disease. Ischemic Heart DiseaseMyocardial infarction and ischemic heart disease are the leading cause of death in the industrial world. Therapies used for treating these diseases are aimed at restoring and/or improving blood flow to ischemic cardiac tissue. Coronary artery bypass grafting and percutaneous coronary interventions are the mainstays of treatment for these patients and significantly reduce morbidity and mortality (Caines et al. 2004). Unfortunately, roughly 10% of all patients are ineligible for these procedures owing to the presence of diffuse or intractable lesions. Furthermore, significant numbers of diabetic patients that undergo these procedures show insufficient improvement. Without treatment, these patients do poorly, with mortality rates of 8% to 10% per year (Syed et al. 2004).Recently, a noninvasive approach aimed at promoting growth of new coronary blood vessels has been proposed to treat patients who are not eligible for coronary artery bypass grafting and percutaneous coronary interventions. This strategy, termed pharmacological revascularization or angiogenesis, involves either systemic or local administration of proangiogenic agents that promote growth of the established vasculature and/or formation of new coronary blood vessels. The search for molecules that possess this activity is actively underway. Over the past 10 years, it has been realized that expression of a number of known proangiogenic factors can promote coronary vessel growth in animal models. Overexpression of fibroblast growth factor-2 (FGF2), vascular endothelial growth factor-A (VEGF-A), and ...

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Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia

Cited by 115 publications

References 36 publications

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction

Rebuilding the Coronary Vasculature: Hedgehog as a New Candidate for Pharmacologic Revascularization

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