Insulin Prevents Cardiomyocytes From Oxidative Stress–Induced Apoptosis Through Activation of PI3 Kinase/
            <i>Akt</i>

Aikawa, Ryuichi; Nawano, Masao; Gu, Yuchun; Katagiri, Hideki; Asano, Tomohiko; Zhu, Weidong; Nagai, Ryozo; Komuro, Issei

doi:10.1161/01.cir.102.23.2873

Cited by 212 publications

(118 citation statements)

References 32 publications

(50 reference statements)

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“…To determine if A1-CM activated AKT signalling in NRVMs, we monitored phosphorylation states of AKT at various times after A1-CM addition (Figure 4). Western blot analyses showed a strong increase in AKT phosphorylation at all times (15 min–12 h) following the addition of insulin (1 µM; positive control), as expected [40]. One hour after A1-CM treatment, NRVMs showed a significant increase (1.7-fold) in AKT phosphorylation, an effect not seen in cells exposed to A1-CM(GW).…”

Section: Resultssupporting

confidence: 67%

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Middleton

Rogers

Couto

et al. 2018

J of Extracellular Vesicle

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Newts can regenerate amputated limbs and cardiac tissue, unlike mammals which lack broad regenerative capacity. Several signaling pathways involved in cell proliferation, differentiation and survival during newt tissue regeneration have been elucidated, however the factors that coordinate signaling between cells, as well as the conservation of these factors in other animals, are not well defined. Here we report that media conditioned by newt limb explant cells (A1 cells) protect mammalian cardiomyocytes from oxidative stress-induced apoptosis. The cytoprotective effect of A1-conditioned media was negated by exposing A1 cells to GW4869, which suppresses the generation of extracellular vesicles (EVs). A1-EVs are similar in diameter (~100–150 nm), structure, and share several membrane surface and cargo proteins with mammalian exosomes. However, isolated A1-EVs contain significantly higher levels of both RNA and protein per particle than mammalian EVs. Additionally, numerous cargo RNAs and proteins are unique to A1-EVs. Of particular note, A1-EVs contain numerous mRNAs encoding nuclear receptors, membrane ligands, as well as transcription factors. Mammalian cardiomyocytes treated with A1-EVs showed increased expression of genes in the PI3K/AKT pathway, a pivotal player in survival signaling. We conclude that newt cells secrete EVs with diverse, distinctive RNA and protein contents. Despite ~300 million years of evolutionary divergence between newts and mammals, newt EVs confer cytoprotective effects on mammalian cardiomyocytes.

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Section: Resultssupporting

confidence: 67%

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Middleton

Rogers

Couto

et al. 2018

J of Extracellular Vesicle

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“…In particular, protection against palmitate-induced apoptosis in clonal ␤-cells provided by unsaturated FA application was PI 3-kinase-dependent (73). In cardiomyocytes, oxidative stress-induced apoptosis was prevented by insulin in a PI 3-kinase/Akt-dependent manner (105), and the cytoprotective effect of PI 3-kinase signaling in this cell type involved enhancement of the mitochondrial ability to accumulate Ca 2ϩ without undergoing terminal depolarization (106). Our data indicate that this pathway also controls the limited opening of the mitochondrial pore, in addition to the full-size form of MPT.…”

Section: Discussionmentioning

confidence: 95%

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Koshkin

Dai

Doucette

et al. 2008

Journal of Biological Chemistry

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Involvement of the mitochondrial permeability transition (MPT) pore in early stages of lipotoxic stress in the pancreatic ␤-cell lines MIN6 and INS-1 was the focus of this study. Both long term (indirect) and acute (direct) effects of fatty acid (FA) application on ␤-cell susceptibility to Ca 2؉ -induced MPT induction were examined using both permeabilized and intact ␤-cells. Long term exposure to moderate (i.e. below cytotoxic) levels of the saturated FA palmitate sensitized ␤-cell mitochondria to MPT induced by Ca 2؉ . Long term exposure to palmitate was significantly a more efficient inducer of MPT than the unsaturated FA oleate, although upon acute application both caused similar MPT activation. Application of antioxidants, inhibitors of the ceramide pathway, or modifiers of membrane fluidity did not protect ␤-cell mitochondria from FA exposure. However, significant protection was provided by co-application of the unsaturated FA oleate in a phosphatidylinositol 3-kinase-dependent manner. Characterization of MPT pore opening in response to moderate palmitate treatment revealed the opening of a unique form of MPT in ␤-cells as it encompassed features of both low and high conductance MPT states. Specifically, this MPT showed solute selectivity, characteristic of a low conductance MPT; however, it affected mitochondrial respiration and membrane potential in a way typical of a high conductance MPT. Activation of the full-size/high conductance form of MPT required application of high levels of FA that reduced growth and initiated apoptosis. These findings suggest that in the ␤-cell, MPTs can act as both initiators of cell death and as versatile modulators of cell metabolism, depending on the mode of the MPT pore induced. Mitochondrial permeability transition (MPT)2 is the calcium (Ca 2ϩ )-dependent opening of a nonspecific pore in the mitochondrial inner membrane in response to a variety of inducers and co-inducers, including inorganic phosphate (P i ), thiol oxidants, fatty acids (FA), and others. Opening of the "full-size" or "high conductance" MPT causes equilibration across the inner membrane of ions and all solutes up to 1.5 kDa, which induces mitochondrial swelling and the release of mitochondrial proteins capable of apoptosis activation (1-5). MPT can also operate in a more "limited size" or "low conductance" mode, which allows passage of only small ions across the inner mitochondrial membrane (6, 7). Because opening of the low conductance MPT does not allow passage of large molecules, but does allow the passage of small ions, mitochondrial ion gradients and energy production are affected. As such, it is thought that the low conductance MPT functions not to induce cell death but to aid in the fine regulation of cell metabolism (6). Extensive evidence documents the high conductance MPT as a cause of generalized mitochondrial dysfunction and cell death, and an important mechanism in disease pathologies such as hepatotoxicity (8), cardiac ischemia/reperfusion (9, 10), and neuronal injury (10, 11). In contrast,...

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“…35 Insulin also has a cardioprotective effect through the activation of antiapoptotic pathways 39 and its ability to limit oxidative stress, 40 thus leading to the consideration of insulin as a protective hormone for cardiomyocytes. Our study suggests that this concept of insulin should be taken with caution in the setting of obesity, since insulin-induced downregulation of M 2 R activity may alter the autonomic control of the heart.…”

Section: Discussionmentioning

confidence: 99%

Insulin downregulates M2-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications

et al. 2004

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OBJECTIVE:To determine whether decreased cardiac parasympathetic activity observed in obesity is due to insulin-induced alterations in cardiac M 2 -muscarinic receptors and/or adenylyl cyclase activity. DESIGN AND METHODS: After incubation with increasing concentrations of insulin, adult rat atrial cardiomyocytes were assayed for M 2 -muscarinic receptor binding density and affinity, and for M 2 R mRNA expression using RT-PCR analysis. Forskolinstimulated adenylyl cyclase activity and its inhibition by carbachol were also assayed, as was endothelial nitric oxide synthase mRNA expression. The effects of insulin on M 2 -muscarinic receptor density and mRNA expression levels were analyzed using the insulin signaling inhibitors rapamycin, wortmanin and PD 098059. RESULTS: Insulin induces a concentration-and time-dependent decrease in expression of the M 2 R mRNA, and in [ 3 H]Nmethylscopolamine binding by the receptor. These effects on the M 2 R mRNA levels and on [ 3 H]N-methylscopolamine binding were prevented by PD 98059, but not by wortmanin or rapamycin. Basal and forskolin-induced cAMP production did not differ, but the inhibition of forskolin-simulated enzyme activity by carbachol was blunted by insulin. No change in the mRNA levels for endothelial nitric oxide synthase was observed. CONCLUSION: In rat atrial cardiomyocytes, insulin markedly alters both the M 2 -muscarinc receptor density, and its mRNA expression through transcriptional regulation and adenylyl cyclase activity. These data suggest that the obesity-associated decrease in cardiac parasympathetic tone may be related to hyperinsulinemia, which could directly contribute to cardiovascular morbidity in obese patients.

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Insulin Prevents Cardiomyocytes From Oxidative Stress–Induced Apoptosis Through Activation of PI3 Kinase/ Akt

Cited by 212 publications

References 32 publications

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Insulin downregulates M2-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications

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