PDK1 coordinates survival pathways and β-adrenergic response in the heart

Abstract

. Here we defined the role of PDK1 in controlling cardiac homeostasis. Cardiac expression of PDK1 was significantly decreased in murine models of heart failure. Tamoxifeninducible and heart-specific disruption of Pdk1 in adult mice caused severe and lethal heart failure, which was associated with apoptotic death of cardiomyocytes and ␤1-adrenergic receptor (AR) downregulation. Overexpression of Bcl-2 protein prevented cardiomyocyte apoptosis and improved cardiac function. In addition, PDK1-deficient hearts showed enhanced activity of PI3-K␥, leading to robust ␤1-AR internalization by forming complex with ␤-AR kinase 1 (␤ARK1). Interference of ␤ARK1/PI3-K␥ complex formation by transgenic overexpression of phosphoinositide kinase domain normalized ␤ 1 -AR trafficking and improved cardiac function. Taken together, these results suggest that PDK1 plays a critical role in cardiac homeostasis in vivo by serving as a dual effector for cell survival and ␤-adrenergic response.AGC kinase ͉ apoptosis ͉ heart failure ͉ receptor internalization H eart failure, a major cause of morbidity and mortality worldwide, is a clinical syndrome in which the heart is incapable of pumping blood at a rate commensurate with systemic demands (1). Injurious stresses from extrinsic or intrinsic origins trigger the complex intracellular signaling pathways in cardiomyocytes and thereby activate the compensatory mechanisms involving alterations in survival and growth signals, calcium handling, and energy production (2). Simultaneously, the sympathetic nervous, reninangiotensin-aldosterone, and cytokine systems are activated to cope with a decline in cardiac performance. Although these compensatory systems initially maintain cardiac function within a physiological range, prolonged activation of these systems paradoxically leads to cardiac damage and worsens clinical prognosis (2). Therefore, for the elucidation of the pathophysiology of heart failure, it is very important to dissect the inherent complexity of intracellular signaling pathways that coordinate the cellular homeostasis and neurohumoral responses in cardiomyocytes.The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a member of the AGC serine/threonine kinase family that functions downstream of phosphoinositide 3-kinase (PI3-K) and activates several AGC kinases, including Akt, p70 ribosomal S6 kinase (p70S6K), and serum-and glucocorticoid-induced protein kinase 1 (SGK1), by phosphorylating these enzymes at their activation loops (3). The physiological functions of PDK1 have been investigated by targeted disruption of Pdk1 gene. Mouse embryos systemically deficient for Pdk1 were lethal during early embryogenesis, displaying multiple abnormalities that included lack of somites, forebrain, and neural crest-derived tissues (4). Alessi et al. (5) recently generated striated muscle-specific PDK1 conditional knockout mice (PDK1-MCKCre) by crossing mice harboring a ''floxed'' Pdk1 allele with transgenic mice expressing Cre recombinase under the control of the muscle creatine kinase (MC...

Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice

“…In two DCM samples, PDK1 levels were low but both total Akt and Akt S473 phosphorylation levels became high. These observations suggest that a mechanism similar to that in Pdk1-deficient mice may exist in some DCM patients (45). Therefore, a novel approach to enhancing mTORC2-Akt activity may be developed to treat human DCM, as seen in Pdk1-deficient mice.…”

Mechanisms of Cardiovascular Homeostasis and Pathophysiology – From Gene Expression, Signal Transduction to Cellular Communication –

“…When Pdk1 is disrupted in the hearts of tamoxifen-inducible and heart-specific Pdk1 knockout mice at the age of 10 weeks, they show severe and lethal cardiac dysfunction in spite of the unchanged size of cardiomyocytes. 28 Mechanistically, loss of Pdk1 enhanced the susceptibility of cardiomyocytes to apoptosis, and enhanced PI3-K γ activity, which consequently led to robust downregulation of β1-adrenergic receptor and contractile dysfunction. Therefore, besides the fundamental role in promoting cell growth and survival, PDK1 plays a unique and essential role in accommodating the β-adrenergic response to prevent cardiac decompensation (Figure 2).…”

Molecular Mechanisms of Cardiovascular Toxicity of Targeted Cancer Therapeutics

“…PDK1 deletion led to profound heart failure. 39 The PI3K/Akt pathway converges on mTOR, which is a central regulator of cell growth, including cardiomyocyte growth, acting by regulating the protein translation machinery (mTOR complex 1 or mTORC1) and Akt phosphorylation at Ser473 (mTORC2; Figure 3). 40 Indeed, mTOR is a convergence point for progrowth pathways (including not only PI3K/Akt but also the Ras-Raf-ERK-RSK pathway, which activate mTOR), and antigrowth pathways including AMPK and GSK-3, as well as hypoxia, energy deprivation, and reduced abundance of amino acids (all of which inhibit mTORC1 via activation of the tuberous sclerosis [Tsc1/2] complex; Figure 3).…”