Adiponectin is required for cardiac MEF2 activation during pressure overload induced hypertrophy

Dadson, Keith; Turdi, Subat; Hashemi, Sarah; Zhao, Jiahui; Polidovitch, Nazar; Beca, Sanja; Backx, Peter H.; McDermott, John C.; Sweeney, Gary

doi:10.1016/j.yjmcc.2015.06.020

Cited by 27 publications

(28 citation statements)

References 47 publications

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“…7O). Because Adipoq and Retn are heart failure-related Pparg targets (44,45) that are induced by serine 273 phosphorylation-deficient PPARG-S273A (40), these data are compatible with the notion that cardioprotective GRK2 inhibition could involve the suppression of Pparg-dependent cardiolipotoxic gene expression by enhanced ERK-mediated serine 273 phosphorylation and the inactivation of Pparg.…”

Section: Grk2 Inhibition By Grkinh Prevents the Dysfunctional Cardiacsupporting

confidence: 70%

“…Several heart failure-related Pparg targets are inhibited by ERK-dependent Pparg inactivation (36,40) with GRKInh, such as Adipoq (44,51,52) and Retn (45,53). By generating Tg-UCP1 mice with myocardium-specific UCP1 expression, our study identified UCP1 as a heart failure-related ERK-regulated Pparg target (36,47), which was also down-regulated upon GRK2 inhibition (Fig.…”

Section: Discussionmentioning

confidence: 72%

“…The accumulation of palmitate further promotes pro-apoptotic signaling and inhibits the pro-survival ERK axis (16). As a result, there is an enhanced expression of heart failure-associated Pparg targets that are triggered by ERK inhibition (36,40), such as Adipoq (44,51,52), Retn (45,53), and Ucp1. Ensuing cardiomyocyte death and remodeling and impaired cardiac energy generation due to mitochondrial uncoupling could further aggravate the symptoms of heart failure (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Fig. 14, B and E) because Adipoq is required for pro-hypertrophic signaling during pressure overload (44).…”

Section: Down-regulation Of Endogenous Ucp1 Retards the Development Omentioning

confidence: 98%

“…Heart Failure Model-Although previous studies have provided evidence for the involvement of Adipoq and Retn in heart failure pathogenesis of patients and animal models (44,45,(51)(52)(53), the role of Ucp1 up-regulation in cardiac dysfunction is less clear. Notably, the onset of heart failure signs in different heart failure models was characterized by a strong cardiac Ucp1 up-regulation (cf.…”

Section: Down-regulation Of Endogenous Ucp1 Retards the Development Omentioning

confidence: 99%

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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

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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...

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Section: Grk2 Inhibition By Grkinh Prevents the Dysfunctional Cardiacsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

“…Fig. 14, B and E) because Adipoq is required for pro-hypertrophic signaling during pressure overload (44).…”

Section: Down-regulation Of Endogenous Ucp1 Retards the Development Omentioning

confidence: 98%

Section: Down-regulation Of Endogenous Ucp1 Retards the Development Omentioning

confidence: 99%

See 3 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

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Adiponectin Regulation and Function

Han

Judd

2018

Comprehensive Physiology

521

370

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Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK), and increased peroxisome proliferator-activated receptor alpha (PPARα) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. © 2017 American Physiological Society. Compr Physiol 8:1031-1063, 2018.

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