Inhibition of G-protein-coupled Receptor Kinase 2 (GRK2) Triggers the Growth-promoting Mitogen-activated Protein Kinase (MAPK) Pathway

Fu, Xuebin; Koller, Samuel; Alla, Joshua Abd; Quitterer, Ursula

doi:10.1074/jbc.m112.428078

Cited by 36 publications

(72 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transgenic mice were generated as described (12) with minor modifications. Briefly, for the generation of transgenic mice with myocardium-specific expression of FASN, we constructed a transgene that placed the FASN cDNA under the control of the ␣-myosin heavy chain (␣-MHC) promoter (12).…”

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

“…Briefly, for the generation of transgenic mice with myocardium-specific expression of FASN, we constructed a transgene that placed the FASN cDNA under the control of the ␣-myosin heavy chain (␣-MHC) promoter (12). For the generation of transgenic mice with myocardium-specific expression of UCP1 (uncoupling protein-1), PPARG, and PPARG-S273A (isoform-1, which lacks amino acids 1-28 of isoform-2; serine 273 refers to the numbering of isoform-2), a similar approach was used.…”

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

“…Immunohistological detection of Fasn (FASN) was performed with affinity-purified polyclonal antibodies as described (11). Methods describing Oil Red O staining, immunofluorescence detection of proteins, and immunohistology for activated phospho-ERK1/2 in paraffin sections or cryosections have been described previously (11,12). Immunohistology sections were imaged with a Leica DMI6000 microscope equipped with a DFC420 camera, and immunofluorescence imaging was performed with a Leica (TCS) confocal laser microscope.…”

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

“…For generation of transgenic Tg-PPARG and Tg-PPARG-S273A mice, fertilized oocytes from non-transgenic and Tg-GRKInh mice (transgenic mice with myocardium-specific expression of GRKInh, a GRK2-specific peptide inhibitor with the peptide sequence MAKFERLQTVTNYFITSE) were used. Transgenic mice with myocardium-specific expression of GRKInh or human RKIP (PEBP1) were generated and characterized previously (12). Mouse lines in the study were deposited into the JAX repository (The Jackson Laboratory) and have the following strain ID numbers: 911818 (C57BL/6Tg (MHCPEBP1)1 Sjaa); 911822 (C57BL/6Tg(MHCGRK-Inh)1 Sjaa); 911826 (C57BL/6Tg(MHCFASN)1 Sjaa); and 911830 (C57BL/6Tg(MHCUCP1)1 Sjaa).…”

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

“…In search for a treatment approach for the disturbed cardiac substrate metabolism, we focused on the role of GRK2 inhibition because GRK2 inhibition could counteract cardiolipotoxicity by promotion of a cardiomyocyte survival program (12,13) and resensitization of the cardioprotective adiponectin receptor 1 (14 -16). For GRK2 inhibition in vivo, we used GRKInh, a small peptide inhibitor derived from the first intracellular loop of the ␤2-adrenergic receptor (12,17). Our data with GRKInh show that GRK2 inhibition counteracts the heart failure-related cardiac metabolic dysfunction and signs of heart failure of FASN transgenic mice.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor ␥). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.Heart failure is a debilitating syndrome that involves insufficient cardiac performance. Multiple pathomechanisms have been elucidated, but treatment options remain insufficient, and hence the mortality of heart failure is high (1). The causes of heart failure are complex with ischemic heart disease being the most frequently associated condition (2). Co-existing disorders such as diabetes, hypertension, and obesity further deteriorate symptoms (3). Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).Following this concept, we aimed to investigate the impact of improved cardiac substrate availability by generating transgenic mice with myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased express...

show abstract

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%