A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac Hypertrophy

O’Neill, Brian T.; Kim, Jaetaek; Wende, Adam R.; Theobald, Heather; Tuinei, Joseph; Buchanan, Jonathan; Guo, Aili; Zaha, Vlad G.; Davis, Don; Schell, John C.; Boudina, Sihem; Wayment, Benjamin; Litwin, Sheldon E.; Shioi, Tetsuo; Izumo, Seigo; Birnbaum, Morris J.; Abel, E. Dale

doi:10.1016/j.cmet.2007.09.001

Cited by 120 publications

(128 citation statements)

References 47 publications

(63 reference statements)

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…In thinking about candidate proteins downstream of PI3K, other than Akt and TOR, we noted that PKC and  had recently been shown to be required for changes in mitochondrial metabolism in the heart following exercise (O'Neill et al, 2007). There are important differences between this system and the effect of NRG and IGF on mitochondria biogenesis, in that in the study by O'Neill and colleagues increased mitochondrial function was not accompanied by changes in mitochondria amount or mtDNA copy number.…”

Section: Discussionmentioning

confidence: 94%

“…In a recent report, it was shown that the increase in fatty acid oxidation and TCA-cycle activity following exercise-induced cardiac hypertrophy in mice is dependent on PI3K, independent of TOR and dependent on PKC and PKC (O'Neill et al, 2007). We therefore investigated whether PKC is involved in the increase in mitochondrial gene expression stimulated by NRG+IGF.…”

Section: Nrg and Igf Cooperate To Affect Mitochondrial Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

Echave

Machado-da-Silva

Arkell

et al. 2009

Journal of Cell Science

View full text Add to dashboard Cite

Cells generate new organelles when stimulated by extracellular factors to grow and divide; however, little is known about how growth and mitogenic signalling pathways regulate organelle biogenesis. Using mitochondria as a model organelle, we have investigated this problem in primary Schwann cells, for which distinct factors act solely as mitogens (neuregulin) or as promoters of cell growth (insulin-like growth factor 1; IGF1). We find that neuregulin and IGF1 act synergistically to increase mitochondrial biogenesis and mitochondrial DNA replication, resulting in increased mitochondrial density in these cells. Moreover, constitutive oncogenic Ras signalling results in a further increase in mitochondrial density. This synergistic effect is seen at the global transcriptional level, requires both the ERK and phosphoinositide 3-kinase (PI3K) signalling pathways and is mediated by the transcription factor ERRα. Interestingly, the effect is independent of Akt-TOR signalling, a major regulator of cell growth in these cells. This separation of the pathways that drive mitochondrial biogenesis and cell growth provides a mechanism for the modulation of mitochondrial density according to the metabolic requirements of the cell.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Nrg and Igf Cooperate To Affect Mitochondrial Gene Expressionmentioning

confidence: 99%

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

Echave

Machado-da-Silva

Arkell

et al. 2009

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…UCP3 can protect muscle cells against mitochondrial ROS and oxidative damage [30], and overexpression of Tfam protected the heart against mitochondrial respiratory defects and cardiac dysfunction in a setting of myocardial infarction [36]. In addition, it was previously shown that isolated mitochondria from caPI3K mice (basal conditions) had increased mitochondrial enzymatic activity, associated with increased fatty acid oxidative capacity [37].…”

Section: Discussionmentioning

confidence: 99%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

show abstract

“…[51][52][53][54] PI3K(p110␣) has also been reported to differentially regulate metabolism genes in ventricular tissue. 55 Further studies are required to examine the functional consequence of these alterations in gene expression.…”

Section: Discussionmentioning

confidence: 99%

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Pretorius

Woodcock

et al. 2009

The American Journal of Pathology

Self Cite

160

133

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110␣) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110␣) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult (ϳ4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice (ϳ15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF , suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110␣) and AF. (Am J Pathol

show abstract

A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac Hypertrophy

Cited by 120 publications

References 47 publications

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Contact Info

Product

Resources

About