Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFκB activation in vivo

Ha, Tuanzhu; Li, Yuehua; Gao, Xiang; McMullen, Julie R.; Shioi, Tetsuo; Izumo, Seigo; Kelley, Jim; Zhao, Aiqiu; Haddad, Georges E.; Williams, David L.; Browder, I. William; Kao, Race L.; Li, Chuanfu

doi:10.1016/j.freeradbiomed.2005.08.002

Cited by 77 publications

(47 citation statements)

References 37 publications

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“…This is in agreement with previous studies showing strong activation of Akt (10,42), ERK1/2, and p38 MAPK during the development of cardiac hypertrophy (22,23). We (19) have also recently shown that PI3K/Akt signaling activation participate in the development of cardiac hypertrophy in vivo. Nevertheless, one study (49) has shown a drastic increase in the p38 MAPK activity but not that of ERK1/2; however, their assessment was performed 2 days after the induction of cardiac hypertrophy.…”

Section: Basal Regulation Of Potassium Channels By Mapk and Pi3ksupporting

confidence: 94%

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Teos¹,

Zhao²,

Alvin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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The potassium channels IK and IK1, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on IK and IK1 through mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10 Ϫ8 M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal IK activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on IK and IK1. We conclude that basal IK and IK1 are positively maintained by steady-state Akt and ERK activities.

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Section: Basal Regulation Of Potassium Channels By Mapk and Pi3ksupporting

confidence: 94%

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Teos¹,

Zhao²,

Alvin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Moreover, cardiac-specific expression of a constitutively active form of Akt, a primary downstream effector of PI3K, induces significant cardiac hypertrophy in transgenic mice (Matsui et al, 2002;Shioi et al, 2002). Furthermore, the PI3K-Akt signaling pathway has been implicated in multiple forms of hypertrophy both in vivo and in vitro (Ha et al, 2005;Kenessey and Ojamaa, 2006). Collectively, these data suggest a role for the PI3K-Akt signaling pathway in the development of cardiomyocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 83%

Calcineurin Activation Is Not Necessary for Doxorubicin-Induced Hypertrophy in H9c2 Embryonic Rat Cardiac Cells: Involvement of the Phosphoinositide 3-Kinase-Akt Pathway

Merten

Jiang²,

Feng³

et al. 2006

J Pharmacol Exp Ther

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The calcium/calmodulin-dependent phosphatase calcineurin has been shown to be both necessary and sufficient to induce cardiac hypertrophy in vivo and in vitro. Treatment with the antineoplastic agent doxorubicin (DOX) was shown to activate calcineurin signaling in H9c2 rat cardiac muscle cells; however, the effect of this activation on hypertrophy was not investigated. Therefore, the present study was undertaken to examine the involvement of calcineurin activation in DOX-induced cardiac cell hypertrophy. H9c2 cells were treated with 1 M DOX for 2 h following pretreatment with and in the presence of calcineurin inhibitors cyclosporine A (CsA) or FK506 (tacrolimus). Subsequent analysis of calcineurin signaling and cellular hypertrophy was performed 8 to 48 h after the treatment. DOX treatment activated calcineurin signaling and resulted in cellular hypertrophy as assessed by an increase in cell volume and protein content per cell. Inhibition of calcineurin with CsA or FK506 blocked DOX-induced calcineurin signaling. However, this inhibition did not prevent the DOX-induced hypertrophic response in H9c2 cells. Further evaluation of the possible signaling pathways involved in DOX-induced H9c2 cellular hypertrophy revealed that DOX treatment resulted in phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, the DOXinduced hypertrophic response was blunted by LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a specific inhibitor for PI3K. These results demonstrate that, although calcineurin is activated by DOX treatment, it is not necessary for DOX-induced hypertrophy in H9c2 cells. Rather, the PI3K-Akt signaling pathway seems to be more critically involved in DOX-induced hypertrophy.

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“…Knockdown of Atg7 by Ad-Atg7-RNAi inhibits autophagy in rat neonatal cardiomyocytes and then induces cardiomyocyte hypertrophy with typical characteristics. 29 Rapamycin, a potent activator of autophagy, prevents cardiac hypertrophy induced by thyroid hormone treatment, 35 or aortic banding, 36 and regresses existing cardiac hypertrophy. 37 These suggest that a decrease in autophagy at the hypertrophied state facilitates cardiac hypertrophic response.…”

Section: Autophagy In Cardiac Hypertrophymentioning

confidence: 99%

The role of autophagy in the heart

Kyoi²,

et al. 2008

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Autophagy has evolved as a conserving process that uses bulk degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In the heart, autophagy is important for the turnover of organelles at low basal levels under normal conditions and it is upregulated in response to stresses such as ischemia/reperfusion and in cardiovascular diseases such as heart failure. Cardiac remodeling involves increased rates of cardiomyocyte cell death and precedes heart failure. The simultaneously occurring multiple features of failing hearts include not only apoptosis and necrosis but also autophagy as well. However, it has been unclear as to whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for failing cardiomyocytes. The functional role of autophagy during ischemia/reperfusion in the heart is complex. It has also been unclear whether autophagy is protective or detrimental in response to ischemia/reperfusion in the heart. In this review, we will summarize the role of autophagy in the heart under both normal conditions and in response to stress.

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Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFκB activation in vivo

Cited by 77 publications

References 37 publications

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Calcineurin Activation Is Not Necessary for Doxorubicin-Induced Hypertrophy in H9c2 Embryonic Rat Cardiac Cells: Involvement of the Phosphoinositide 3-Kinase-Akt Pathway

The role of autophagy in the heart

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