Protein Kinase C Contributes to the Maintenance of Contractile Force in Human Ventricular Cardiomyocytes

Molnár, Andrea; Borbély, Attila; Czuriga, Dániel; Ivetta, Siket M.; Szilágyi, Szabolcs; Hertelendi, Zita; Pásztor, Enikő T.; Balogh, Agnès; Galajda, Zoltán; Szerafin, Tamás; Jaquet, Kornélia; Papp, Zoltán; Édes, István; Tóth, Attila

doi:10.1074/jbc.m807600200

Cited by 12 publications

(12 citation statements)

References 46 publications

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“…mTORC2 also plays a role in cardiac hypertrophy, 10 since it controls the actin cytoskeleton and activates Akt and PKCα, which has been shown to maintain contractile force by associating with troponin I in myocytes. 34 The effect of mTOR on the expression of both fetal and constitutive hypertrophy genes is not well understood. However mTORC1 and 2 may contribute to the hypertrophic changes observed in the hypercholesterolemic myocardium.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

Glazer¹,

Osipov²,

Clements³

et al. 2009

Cell Cycle

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Nutritional excess and hyperlipidemia increase the heart’s susceptibility to ischemic injury. Mammalian target of rapamycin (mTOR) controls the cellular response to nutritional status and may play a role in ischemic injury. To explore the effect of hypercholesterolemia on cardiac mTOR signaling, we assessed mTOR signaling in hypercholesterolemic swine (HC) that are also susceptible to increased cardiac ischemia-reperfusion injury. Yucatan pigs were fed a high-fat/high-cholesterol diet for 4 weeks to induce hypercholesterolemia, and mTOR signaling was measured by immunoblotting and immunofluorescence in the non-ischemic left ventricular area. Total myocardial mTOR and raptor levels were markedly increased in the HC group compared to the normocholesterolemic group, and directly correlated with serum cholesterol levels. mTOR exhibited intense perinuclear staining in myocytes only in the HC group. Hypercholesterolemia was associated with hyperactive signaling upstream and downstream of both mTOR complexes, including myocardial Akt, S6K1, 4EBP1, S6 and PKC-alpha, increased levels of cardiac hypertrophy markers, and a trend toward lower levels of myocardial autophagy. Hypercholesterolemia can now be added to the growing list of conditions associated with aberrant mTOR signaling. Hypercholesterolemia produces a unique profile of alterations in cardiac mTOR signaling, which is a potential target in cardiac diseases associated with hypercholesterolemia and nutritional excess.

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Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

Glazer¹,

Osipov²,

Clements³

et al. 2009

Cell Cycle

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“…Paradoxically, the increase in myofilament-associated PKC␣ following an acute ischemic challenge may also represent a compensatory change. Molnar and colleagues (46) found that PKC␣ maintains cardiac myofilament force development under conditions that occur during I/R. By contrast, ShintaniIshida and Yoshida (55) report that post-I/R activation of PKC␣ at the sarcoplasmic reticulum exacerbates I/R damage, arguing for subcellular-specific effects of PKC␣.…”

Section: Discussionmentioning

confidence: 99%

“…Among the isoforms that are activated by overexpression of FGF2 in the mouse heart that may also phosphorylate targets modulating cardiac function are PKCε and ␣ (1,5,9,17,22,27,33,34,46,53). PKCε has been shown to localize to the cross-striated structures when activated (17, 27, 52) and is known to phosphorylate troponin I (TnI) and troponin T (TnT), as well as myosin light chain and myosin binding protein C (MyBP-C), which modulates calcium sensitivity of the myofilaments in the heart (34).…”

mentioning

confidence: 99%

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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“…37 Dempsey et al 38 found that cardiac myocytes contain at least six different PKC isozymes but preconditioning results in activation of only two isozymes, PKC-d and PKC-e. Quantitation of PKC-isoform expression showed the dominance of the Ca 2+ -dependent PKCa over PKC-d and PKC-e. PKC-a is the single isozyme that translocates to the contractile system on Ca 2+ stimulation in the rat heart, suggesting a unique physiological role for PKCa in the Ca 2+ -dependent regulation of myofibrillar contractility. 39,40 The a-subunit of Gq is a well-established mediator of hypertrophic growth in neonatal cardiomyocytes and in mouse hearts. Studies have found that although aortic AR-a 1A , AR-a 1B and AR-a 1D are associated with Gqa, AR-a 1B is also linked to Goa and the couple AR-a 1B -Goa mediates the contractile response of rat aorta.…”

Section: Discussionmentioning

confidence: 99%

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

et al. 2010

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To test the hypothesis that nonselective blockade of adrenergic receptor (AR) subtypes is superior to selective blockade of AR subtypes in suppressing left ventricular (LV) remodeling induced by hypertension. Sixty-four spontaneously hypertensive rats (SHR) were randomly divided into four groups: bisoprolol-treated, propranolol-treated, carvedilol-treated and no treatment groups (n¼16, each). Sixteen Wistar-Kyoto (WKY) rats served as a control group. Echocardiography and cardiac catheterization were carried out to record the mitral flow velocity ratio of E wave to A wave (E/A), LV mass index (LVMI), maximal rising (dp/dt max ) and falling (Àdp/dt max ) rate of the LV pressure and LV relaxation time constant (s). The mRNA and protein expression levels of AR, protein kinase(PK) and G-protein subtypes, intracellular free calcium (Ca 2+ ) concentration and cardiocyte apoptoisis rate were determined. Three drug-treated groups showed higher velocity ratio of E wave to A wave (E/A) and Àdp/dt max and lower systolic blood pressure (SBP), LVMI, s, apoptosis rate and intracellular free Ca 2+ concentration than the no treatment group. The mRNA expression levels of AR-a 1B in the carvedilol group were significantly lower than the other two drug-treated groups. The mRNA expression levels of AR-b 1 , AR-b 2 and Gsa were significantly higher in the three drug-treated groups than in the no treatment group, with the expression levels of AR-b 2 being the highest in the carvedilol-treated group. The protein expression levels of PKA and PKC subtype a and d were lower in the three drug-treated groups than in the no treatment group. Overall blockade of AR subtypes is not superior to selective blockade of AR subtypes in suppressing LV remodeling in SHR. Although carvedilol is the most effective in attenuating cardiocyte apoptosis, normalizing AR-a 1B and Gsa expression and increasing AR-b 2 expression.

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Protein Kinase C Contributes to the Maintenance of Contractile Force in Human Ventricular Cardiomyocytes

Cited by 12 publications

References 46 publications

Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

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

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

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