Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure

Nienaber, Jeffrey J.; Tachibana, Harukuni; Prasad, Sathyamangla V. Naga; Esposito, Giovanni; Wu, Dianqing; Rockman, Howard A.

doi:10.1172/jci200318213

Cited by 38 publications

(69 citation statements)

References 33 publications

(60 reference statements)

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“…These results are consistent with our recent studies showing that preventing the local generation of phosphatidylinositols by PI3K within the activated receptor complex preserves bAR signaling and ameliorates cardiac dysfunction in a variety of animal models of heart failure (13,26,27). While we cannot exclude that early bAR hyperfunction might be involved in the development of the maladaptive phenotype, our approach of displacing the PI3K from bARK1 prevented many pathological features induced by pressure overload by normalizing bAR signaling in a manner similar to the beta blocker metoprolol.…”

Section: Figuresupporting

confidence: 93%

“…bARK1 associates with multiple isoforms of the enzyme PI3K to form a stable cytosolic complex that is recruited to activated bARs following prolonged receptor stimulation (13,26,27). Increased membrane-targeted PI3K activity is associated with bAR dysfunction in models of heart failure (13).…”

Section: Figurementioning

confidence: 99%

“…To determine whether abnormalities in bAR function can be experimentally dissected from the growth response induced by pressure overload and to test whether normalizing bAR signaling is associated with rescue of the hypertrophy-independent pathological phenotype induced by iTAC, we applied intermittent pressure overload for only 7 days in WT mice and transgenic mice with cardiac-specific overexpression of catalytically inactive PI3Kg (iTACg inact mice; Figure 5A and Supplemental Figure 1C). We have previously shown that overexpression of catalytically inactive PI3Kg (PI3Kg inact ) preserves bAR function in a number of models of heart failure (13,26,27).…”

Section: Figurementioning

confidence: 99%

“…However, the nature of the stress responsible for the induction of early bAR abnormalities in pressure-overloaded hearts remains unclear. To test whether different levels of catecholamines during the acute phases of stress might explain the different phenotype observed upon swimming or intermittent pressure overload, we measured plasma levels of epinephrine and norepinephrine in the hearts of WT swimming, iTAC, and iTACg inact mice at the termination of the training sessions and after 12 hours of rest, with or without pretreatment with metoprolol ( Figure 10) (13,26,27). Interestingly, in animals from all the groups terminated immediately after 90 minutes of stress we observed an equal, significant increase in the levels of epinephrine and norepinephrine ( Figure 10, A and B) that was similarly reversed by 12 hours of rest.…”

Section: Figurementioning

confidence: 99%

“…Therefore, a concept of continuous progression from compensated hypertrophy toward heart failure has recently led to proposing cardiac hypertrophy as an early therapeutic target (3,6,7). However, the blockade of the growth response is not always beneficial (8)(9)(10)(11)(12), and importantly, inhibition of the growth response is not absolutely required to ameliorate cardiac dysfunction (13,14). Moreover, hypertrophy is also a response of the heart to physiological stresses such as endurance exercise, but the athlete's heart does not progress to heart failure.…”

Section: Introductionmentioning

confidence: 99%

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Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction

Perrino¹

2006

Journal of Clinical Investigation

226

162

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For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered b-adrenergic receptor (bAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by bAR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.

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Section: Figuresupporting

confidence: 93%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction

Perrino¹

2006

Journal of Clinical Investigation

226

162

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MicroRNA‐214 Is Upregulated in Heart Failure Patients and Suppresses XBP1‐Mediated Endothelial Cells Angiogenesis

et al. 2015

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More and more miRNAs have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiovascular diseases including the miR-199a/214 cluster. However, the signature of circulating miR-214 expression and its possible roles during the development of heart failure has been less well studied. In this study, we elucidated the biological and clinical significance of miR-214 dysregulation in heart failure. Firstly, circulating miR-214 was measured by quantitative PCR, and we found that miR-214 was upregulated in the serum of chronic heart failure patients, as well as in hypertrophic and failing hearts of humans and mice. Adeno-associated virus serotype 9 (AAV9)-mediated miR-214 silencing attenuates isoproterenol (ISO) infusion-induced cardiac dysfunction and impairment of cardiac angiogenesis in mice. Mechanistically, miR-214 overexpression reduces angiogenesis of HUVECs by targeting XBP1, an important transcription factor of unfolded protein response, and XBP1 silencing decreases HUVECs proliferation and angiogenesis similar to miR-214 overexpression. Furthermore, ectopic expression of XBP1 enhances endothelial cells proliferation and tube formation, and reverses anti-angiogenic effect of miR-214 over expression. All these findings suggest that miR-214 is an important regulator of angiogenesis in heart in vitro and in vivo, likely via regulating the expression of XBP1, and demonstrate that miR-214 plays an essential role in the control/inhibition of cardiac angiogenesis.

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Proteomic profiling reveals comprehensive insights into adrenergic receptor‐mediated hypertrophy in neonatal rat cardiomyocytes

Liu

Zhang

et al. 2009

Proteomics Clinical Apps

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Myocardial adrenergic receptors (ARs) play important roles in cardiac hypertrophy. However, the detailed molecular mechanism of AR-mediated cardiac hypertrophy remains elusive to date. To gain full insight into how ARs are involved in the regulation of cardiac hypertrophy, protein expression profiling was performed with comparative proteomics approach on neonatal rat cardiomyocytes. Forty-six proteins were identified as differentially expressed in hypertrophic cardiomyocytes induced by AR stimulation. To better understand the biological significance of the obtained proteomic data, we utilized the ingenuity pathway analysis tool to construct biological networks and analyze function and pathways that might associate with AR-mediated cardiac hypertrophy. Pathway analysis strongly suggested that ROS may be involved in the development of AR-mediated cardiac hypertrophy, which was then confirmed by further experimentation. The results showed that a marked increase in ROS production was detected in AR-mediated cardiac hypertrophy and blocking of ROS production significantly inhibited AR-mediated cardiac hypertrophy. We further proved that the ROS production was through NADPH oxidase or the mitochondrial electron transport chain and this ROS accumulation resulted in activation of extracellular signal-regulated kinase 1/2 leading to AR-mediated cardiac hypertrophy. These experimental results support the hypothesis, from the ingenuity pathway analysis, that AR-mediated cardiac hypertrophy is associated with the dysregulation of a complicated oxidative stress-regulatory network. In conclusion, our results provide a basis for understanding the detailed molecular mechanisms of AR-mediated cardiac hypertrophy.

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Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure

Cited by 38 publications

References 33 publications

Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction

Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction

MicroRNA‐214 Is Upregulated in Heart Failure Patients and Suppresses XBP1‐Mediated Endothelial Cells Angiogenesis

Proteomic profiling reveals comprehensive insights into adrenergic receptor‐mediated hypertrophy in neonatal rat cardiomyocytes

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