Role of p90 Ribosomal S6 Kinase–Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium

Itoh, Seigo; Ding, Bo; Shishido, Tetsuro; Lerner-Marmarosh, Nicole; Wang, Nadan; Maekawa, Naoya; Berk, Bradford C.; Takeishi, Yasuchika; Yan, Chen; Blaxall, Burns C.; Abe, Jun

doi:10.1161/circulationaha.105.578278

Cited by 32 publications

(41 citation statements)

References 55 publications

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“…However, it remains unclear how prorenin was activated to renin in cardiac myocytes. Recently, the expression of kallikrein-like proreninconverting enzyme (PRECE) was shown to be increased in ischemic and diabetic myocardium and to contribute to the activation of the RAS in these conditions (28). Although the types of cardiac cells that express PRECE and the cellular localization were not determined in that study, the involvement of PRECE in our studies is possible.…”

Section: Discussionmentioning

confidence: 75%

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

Singh¹,

Le²,

Bhat³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

135

138

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The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT(1)) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.

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Section: Discussionmentioning

confidence: 75%

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

Singh¹,

Le²,

Bhat³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

135

138

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“…Diabetes mellitus (DM) was induced in male FVB mice (5 to 8 weeks old and 25 to 35 g body weight, The Jackson Laboratory, Bar Harbor, ME) by intraperitoneal injection of STZ (200 mg/kg body weight). 10,11 Tail vein blood glucose samples were measured 6 days after injection to ensure induction of hyperglycemia. As a control, vehicle (0.1 mol/L citrate buffer, pH 4.5) was injected in another group of mice.…”

Section: Streptozotocin (Stz)-induced Hyperglycemia Exacerbates LV Dymentioning

confidence: 99%

Effects of MEK5/ERK5 Association on Small Ubiquitin-Related Modification of ERK5: Implications for Diabetic Ventricular Dysfunction After Myocardial Infarction

Shishido

Woo

Ding

et al. 2008

Circulation Research

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Abstract-Diabetes mellitus (DM) contributes to the exacerbation of left ventricle (LV) dysfunction after myocardial infarction (MI). Activation of ERK5, an atypical mitogen activated protein kinase with transcriptional activity, inhibits apoptosis and LV dysfunction after doxorubicin treatment. SUMOylation has been proposed as a negative regulator of various transcription factors. In the current study, we investigated the role of ERK5-SUMOylation in ERK5 transcriptional activity as well as on DM-mediated exacerbation of LV dysfunction and apoptosis after MI. ERK5 wild-type transcriptional activity was inhibited by Ubc9 (SUMO E2 conjugase) or PIAS1 (E3 ligase), but not in the ERK5-SUMOylation-site defective mutant (K6R/K22R). H 2 O 2 and high glucose, 2 well-known mediators of diabetes, induced ERK5-SUMOylation, and the K6R/K22R mutant, dominant negative form of Ubc9, and siRNA-PIAS1 reversed H 2 O 2 -mediated reduction of ERK5 transcriptional activity in cardiomyocytes, indicating the presence of SUMOylationdependent ERK5 transcriptional repression. Constitutively active form of MEK5␣ (CA-MEK5␣) inhibited ERK5-SUMOylation independent of kinase activity, but dependent on MEK5-ERK5 association. To investigate the pathological role of ERK5-SUMOylation in DM mice after MI, we used cardiac specific CA-MEK5␣ transgenic mice (CA-MEK5␣-Tg). MI was induced in streptozotocin (STZ)-injected (DMϩMI group) or vehicle-injected mice (MI group) by ligating the left coronary artery. The ERK5-SUMOylation was increased in the DMϩMI, but not in the MI group. ERK5-SUMOylation, the exacerbation of LV dysfunction, and the number of TUNEL-positive cells in DMϩMI was significantly inhibited in CA-MEK5␣-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5␣-Tg and non-transgenic littermate control mice. These results demonstrated that ERK5 transcriptional activity is subject to downregulation by diabetes-dependent SUMOylation, which resulted in a proapoptotic condition contributing to poor post-MI LV function.

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“…In view of the proposed involvement of NHE1 activity in the pathogenesis of cardiac ischemic injury (12) and remodeling (13), such findings have led to the consideration of RSK as a potential therapeutic target for cardiac protection (14). Nevertheless, only limited information is available on other RSK substrates and functions in the heart, which may include roles in the phosphorylation of the inhibitory subunit of cardiac troponin I (cTnI) (15), the induction of prorenin-converting enzyme in ischemic and diabetic myocardium (16) of cardiac repolarization in response to reactive oxygen species (17).…”

mentioning

confidence: 99%

Novel Role for p90 Ribosomal S6 Kinase in the Regulation of Cardiac Myofilament Phosphorylation

Cuello

Bardswell

Haworth

et al. 2011

Journal of Biological Chemistry

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In myocardium, the 90-kDa ribosomal S6 kinase (RSK) is activated by diverse stimuli and regulates the sarcolemmal Na ؉ /H ؉ exchanger through direct phosphorylation. Only limited information is available on other cardiac RSK substrates and functions. We evaluated cardiac myosin-binding protein C (cMyBP-C), a sarcomeric regulatory phosphoprotein, as a potential RSK substrate. In rat ventricular myocytes, RSK activation by endothelin 1 (ET1) increased cMyBP-C phosphorylation at Ser 282 , which was inhibited by the selective RSK inhibitor D1870. Neither ET1 nor D1870 affected the phosphorylation status of Ser 273 or Ser 302 , cMyBP-C residues additionally targeted by cAMP-dependent protein kinase (PKA). Complementary genetic gain-and loss-of-function experiments, through the adenoviral expression of wild-type or kinase-inactive RSK isoforms, confirmed RSK-mediated phosphorylation of cMyBP-C at Ser 282 . Kinase assays utilizing as substrate wild-type or mutated (S273A, S282A, S302A) recombinant cMyBP-C fragments revealed direct and selective Ser 282 phosphorylation by RSK. Immunolabeling with a Ser(P) 282 antibody and confocal fluorescence microscopy showed RSKmediated phosphorylation of cMyBP-C across the C-zones of sarcomeric A-bands. In chemically permeabilized mouse ventricular muscles, active RSK again induced selective Ser 282 phosphorylation in cMyBP-C, accompanied by significant reduction in Ca 2؉ sensitivity of force development and significant acceleration of cross-bridge cycle kinetics, independently of troponin I phosphorylation at Ser 22 /Ser 23 . The magnitudes of these RSK-induced changes were comparable with those induced by PKA, which phosphorylated cMyBP-C additionally at Ser 273 and Ser 302 . We conclude that Ser 282 in cMyBP-C is a novel cardiac RSK substrate and its selective phosphorylation appears to regulate cardiac myofilament function.The 90-kDa ribosomal S6 kinase (p90 RSK or RSK), 3 also known as the mitogen-activated protein kinase-activated protein kinase-1 (MAPKAP-K1) family, comprises three principal isoforms: RSK1 (encoded by the RPS6KA1 gene), RSK2 (RPS6KA3), and RSK3 (RPS6KA2) (1). An additional isoform, RSK4 (RPS6KA6), has also been identified, but evidence suggests that this isoform behaves in an atypical manner in terms of its expression and function (2). All four isoforms are characterized by the presence of two functionally distinct kinase domains, the N-terminal kinase (NTK) and the C-terminal kinase (CTK) (1). RSKs bind and are activated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) through a sequential process that involves ERK-mediated phosphorylation of the CTK, CTK-mediated autophosphorylation of the RSK hydrophobic motif to create a docking site for 3Ј-phosphoinositide-dependent kinase 1 (PDK1), and PDK1-mediated phosphorylation of the NTK (1). Although the only known substrate of the CTK is the RSK hydrophobic motif, multiple cellular substrates are phosphorylated by the NTK, a serine/ threonine kinase of the AGC kinase family (1). Consistent with this, RS...

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Role of p90 Ribosomal S6 Kinase–Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium

Cited by 32 publications

References 55 publications

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

Effects of MEK5/ERK5 Association on Small Ubiquitin-Related Modification of ERK5: Implications for Diabetic Ventricular Dysfunction After Myocardial Infarction

Novel Role for p90 Ribosomal S6 Kinase in the Regulation of Cardiac Myofilament Phosphorylation

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