Acute protection of ischemic heart by FGF-2: involvement of FGF-2 receptors and protein kinase C

Jiang, Zhi‐Sheng; Padua, Raymond R.; Ju, Haisong; Doble, Bradley W.; Jin, Yan; Hao, J. M.; Cattini, Peter A.; Dixon, Ian M.C.; Kardami, Elissavet

doi:10.1152/ajpheart.00290.2001

Cited by 80 publications

(70 citation statements)

References 48 publications

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“…The overexpression of both FGF-1 and FGF-2 have been shown to promote the survival of adult cardiomyocytes in response to ischemic injury in vivo (House et al, 2005;Jiang et al, 2002;Jiang et al, 2004;Palmen et al, 2004), and the cardioprotective effects of FGF-2 in the adult myocardium are mediated through the MAPK pathway (House et al, 2005), the same branch of the FGFR signaling cascade that we have shown in cardiac tissue functions through SHP-2. Interestingly, the specific function of FGF-2 in preventing programmed cell death in response to ischemic insult was shown to be independent of its mitogenic or angiogenic functions, suggesting that FGF-2 is functioning specifically to promote cardiomyocyte cell survival (Jiang et al, 2004).…”

Section: Shp-2 and The Fgf Pathwaysupporting

confidence: 53%

SHP-2 is required for the maintenance of cardiac progenitors

et al. 2007

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The isolation and culturing of cardiac progenitor cells has demonstrated that growth factor signaling is required to maintain cardiac cell survival and proliferation. In this study, we demonstrate in Xenopus that SHP-2 activity is required for the maintenance of cardiac precursors in vivo. In the absence of SHP-2 signaling, cardiac progenitor cells downregulate genes associated with early heart development and fail to initiate cardiac differentiation. We further show that this requirement for SHP-2 is restricted to cardiac precursor cells undergoing active proliferation. By demonstrating that SHP-2 is phosphorylated on Y542/Y580 and that it binds to FRS-2, we place SHP-2 in the FGF pathway during early embryonic heart development. Furthermore, we demonstrate that inhibition of FGF signaling mimics the cellular and biochemical effects of SHP-2 inhibition and that these effects can be rescued by constitutively active/Noonan-syndrome-associated forms of SHP-2. Collectively, these results show that SHP-2 functions within the FGF/MAPK pathway to maintain survival of proliferating populations of cardiac progenitor cells.

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Section: Shp-2 and The Fgf Pathwaysupporting

confidence: 53%

SHP-2 is required for the maintenance of cardiac progenitors

et al. 2007

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“…In addition, increased levels of intracellular ATP during ischemia have been seen when recombinant FGF2 is administered to ischemic hearts (30). Further studies are currently determining whether depressed activity of contractile proteins mediated by PKC␣ during I/R may slow ATP depletion and intracellular calcium overload.…”

Section: Discussionmentioning

confidence: 99%

“…Snap-frozen nonischemic hearts (wild type) were powdered and homogenized in homogenization buffer (25 mM HEPES, pH 7.5, 1% glycerol, 150 mM NaCl, 1% Triton X-100, 5 mM EDTA, 1 mM sodium orthovandate, 25 mM ␤-glycerolphosphate, 50 mM sodium fluoride solid, 0.5 M okadaic acid, diisopropylfluorophosphate, 100 M calpain inhibitor, Pefabloc stock 1 and 2, and Sigma phosphatase inhibitor) as previously described (30,40,41). The homogenate was centrifuged at 13,000 g for 15 min, and the supernatant was collected.…”

Section: Whole Heart Preparation To Detect Fgfr Activationmentioning

confidence: 99%

“…Our laboratory, using gain-of-function and loss-of-function genetic mouse models, has demonstrated that all endogenous FGF2 isoforms are necessary for protection against myocardial infarction (40, 41), whereas HMW and LMW FGF2 isoforms play opposing roles in the recovery of the heart from I/R injury (40, 41). Studies using genetically modified mice with only LMW FGF2 expression (HMWKO), or wild-type mouse hearts with LMW FGF2 exogenously added, have shown that this isoform is protective against postischemic dysfunction (30,40,41), while hearts with only the HMW isoforms (LMWKO), or with HMW FGF2 overexpressed, have significantly lower postischemic cardiac function (40). However, the pathways involved in signal transduction for each isoform subtype during I/R-induced cardiac dysfunction have not yet been elucidated; this information is critical for understanding the actions of FGF2 in the postischemic heart.…”

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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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“…Administration of FGF-2 at the onset of ischemia is reported to reduce injury and attenuate heart enzymes. 17,18 It can be a promising choice of pretreatment in CABG to reduce the ischemic injury of cross-clamp time. Nakamae et al reported that FGF-2 enhanced vascular density in necrotic iliac bone in rabbits.…”

Section: Discussionmentioning

confidence: 99%