Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy

Li, Jinqing; Zhang, Cheng; Xing, Yifan; Janicki, Joseph S.; Yamamoto, Masayuki; Wang, Xing Li; Tang, Dongqi; Cui, Taixing

doi:10.1093/cvr/cvr010

Cited by 80 publications

(66 citation statements)

References 38 publications

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“…(53,54). Consistent with previous observations that Nrf2 deficiency leads to an earlier onset of cardiac pathological remodeling and the subsequent development of heart failure in response to hemodynamic overload or pharmacologically induced cardiac stress (55,56), Wang et al found that the cardiomyocyte-specific overexpression of Nrf2 suppressed myocardial oxidative stress as well as cardiac apoptosis, fibrosis, hypertrophy, and dysfunction in a setting of sustained pressure overload produced by transverse aortic constriction (53). Interestingly, the constitutive activation of Nrf2 increased the steady level of autophagosomes while decreasing ubiquitinated protein levels and ubiquitin-positive protein aggregates in the pressure overloaded heart.…”

Section: Nrf2 In Autophagysupporting

confidence: 89%

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

et al. 2016

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Protein quality control (PQC) acts to minimize the level and toxicity of malfolded proteins in the cell. It is performed by an elaborate network of molecular chaperones and targeted protein degradation pathways. PQC monitors and maintains protein homeostasis or proteostasis in the cells. Whilst chaperones may actively promote refolding of malfolded proteins, the malfolded proteins which cannot be correctly refolded are degraded by the ubiquitin proteasome system (UPS) and the autophagic-lysosome pathway (ALP). The UPS degrades individual misfolded protein molecules, whereas the ALP removes large and less soluble protein aggregates and organelles. Emerging evidence indicates that dysregulated and inadequate PQC play an important role in the pathogenesis of not only classic conformational disease but more common forms of cardiac pathology such as cardiac pathological hypertrophy and heart failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor of cellular defense, appears to regulate the USP and the ALP by directly controlling the expression of UPS-and ALP-related genes. This article highlights an emerging role of Nrf2 in the regulation of intracellular PQC as well as its potential involvement in cardiac pathology.

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Section: Nrf2 In Autophagysupporting

confidence: 89%

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

et al. 2016

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“…Further investigation indicated that miR-221-induced cardiac remodeling is associated with the downregulation of p27, activation of the mTOR pathway, and the subsequent inhibition of autophagy in cardiomyocytes [3]. The p27 gene is robustly expressed in adult cardiomyocytes, and it plays an anti-hypertrophic role in response to adverse stimulations [4][5][6]. Furthermore, p27 was also found to protect cardiomyocytes from apoptosis by inducing autophagy during metabolic stress [7].…”

Section: Cardiac-specific Overexpression Of Mir-222 Induces Heart Faimentioning

confidence: 99%

Cardiac-Specific Overexpression of miR-222 Induces Heart Failure and Inhibits Autophagy in Mice

Chen

Changxin

et al. 2016

Cell Physiol Biochem

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Background: MicroRNAs play a crucial role in the regulation of pathological cardiac remodeling and heart failure. Previously, we found that overexpression of miR-221 induces heart failure in mice. The miR-222 and miR-221 share the same gene cluster, however, the role of miR-222 in the regulation of cardiac function remained ill-defined. Methods and Results: Transgenic mice with cardiac-specific expression of miR-222 (Tg-miR-222) mice were generated. The Tg-miR-222 mice developed significantly enlarged hearts at 4 weeks of age. Transthoracic echocardiograph data indicated that the hearts of Tg-miR-222 mice exhibited an increased left ventricular end-diastolic internal diameter and decreased fractional shortening. We observed that the LC3-II in Tg-miR-222 mice was decreased accompanied with the upregulation of p62, indicating the autophagy inhibition in the hearts of Tg-miR-222 mice. The mTOR pathway, a negative regulator of autophagy, was activated in the hearts of Tg-miR-222 mice. The expression of p27 was downregulated by miR-222 overexpression. Conclusion: Our data indicate that miR-222 overexpression induces heart failure in mice. The downregulation of p27 and the activation of mTOR pathway may be involved in miR-222-induced heart failure and autophagy inhibition. Thus, targeting miR-222 expression may be a therapeutic strategy against pathological cardiac remodeling.

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Section: Oxido-reductive Pathways In Heartmentioning

confidence: 99%

“…Similarly, angiotensin II (Ang II)-induced cardiac hypertrophy (77), and cell death caused by I/R injury (136) were both exacerbated in Nrf2-null mice. In the case of Ang II-induced hypertrophy, a functional interaction between Nrf2 and the cell cycle regulator, p27, in the inhibition of hypertrophy was demonstrated (77). In general, the deleterious effects of Nrf2 ablation upon cardiac function have been ascribed to decreased levels of antioxidant and detoxifying enzymes resulting in excess oxidant-mediated damage after ROS-induced cardiac stress.…”

Section: Oxido-reductive Pathways In Heartmentioning

confidence: 99%

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Brewer

Mustafi

Murray

et al. 2013

Antioxidants & Redox Signaling

106

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Significance: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. Recent Advances: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. Critical Issues: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. Future Directions: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine.

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Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy

Abstract: The Nrf2-p27(kip1) pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure.

Cited by 80 publications

References 38 publications

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

Cardiac-Specific Overexpression of miR-222 Induces Heart Failure and Inhibits Autophagy in Mice

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

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