Faculty Opinions recommendation of A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy.

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2.Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60–70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout.Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

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AN IL-5/EOSINOPHIL DEPENDENT PATHWAY PLAYS A CRUCIAL ROLE IN THE ACUTE REJECTION OF MHC CLASS-II INCOMPATIBLE SKIN GRAFTS.

Transplantation Journal ◽

10.1097/00007890-199904150-00082 ◽

1999 ◽

Vol 67 (7) ◽

pp. S20

Author(s):

A. Le Moine ◽

M. Surquin ◽

F. X. Demoor ◽

V. Flamand ◽

M. Pretolani ◽

...

Keyword(s):

Acute Rejection ◽

Mhc Class Ii ◽

Crucial Role ◽

Class Ii ◽

Skin Grafts ◽

Dependent Pathway

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Faculty Opinions recommendation of Alternative endogenous protein processing via an autophagy-dependent pathway compensates for Yersinia-mediated inhibition of endosomal major histocompatibility complex class II antigen presentation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5528956.5494054 ◽

2010 ◽

Author(s):

Christian Münz

Keyword(s):

Major Histocompatibility Complex ◽

Major Histocompatibility Complex Class ◽

Antigen Presentation ◽

Class Ii ◽

Protein Processing ◽

Complex Class ◽

Histocompatibility Complex ◽

Endogenous Protein ◽

Class Ii Antigen ◽

Dependent Pathway

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Abstract 182: Class I Histone Deacetylase Inhibition Represses the Upregulation of Sodium-Calcium Exchanger Expression in Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.111.suppl_1.a182 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Santhosh K Mani ◽

Olga Chernysh ◽

Mona S Li ◽

Ludivine Renaud ◽

Michael G Janech ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Hdac Inhibitor ◽

Trichostatin A ◽

Class Ii ◽

Class I ◽

Mass Spectrometry Analysis ◽

Therapeutic Modality ◽

Specific Class ◽

Hdac Activity

Background: Histone deacetylases (HDACs) play an important role in the alteration of gene expression during cardiac hypertrophy and failure. Our previous study demonstrated that acetylated Nkx2.5 is associated with the Class I/II HDAC complex, HDAC5/1/2 at the Ncx1 promoter, and deacetylated Nkx2.5 is associated with the transcriptional activator and histone acetylase, p300 in a mutually exclusive manner. Inhibition of HDACs by the Class I/II inhibitor, trichostatin A (TSA) prevents deacetylation of Nkx2.5 and recruitment of p300 to the Ncx1 promoter, thereby repressing its upregulation. Objective: To assess the specific roles of HDAC1, 2 and 5 in the regulation of Ncx1 gene expression and determine the specific Nkx2.5 lysine(s) undergoing acetylation or deacetylation, which mediates Ncx1 upregulation. Results: Treatment of isolated adult cardiomyocytes with the selective class I HDAC inhibitor, BML210, prevented alpha- and beta-adrenergic stimulated upregulation of Ncx1 expression, whereas treatment with the specific class II HDAC inhibitor, dPAHA did not. Interestingly, the HDAC5 knockout prevented NCX1 upregulation after 72 hr trans-aortic constriction (TAC) in mice. In order to determine which Nkx2.5 lysine(s) is deacetylated by HDAC1/2, we performed mass spectrometry analysis. The Nkx2.5 gene contains 15 lysine moieties, and LC-MS/MS analysis demonstrates that Nkx2.5 is acetylated on two conserved lysine residues. Conclusion: Class I HDAC activity is required for Ncx1 expression but not class II HDAC activity (HDAC5). However, the loss of HDAC5 prevents Ncx1 upregulation because it may act as a scaffold to recruit the factors required for Ncx1 promoter activation. These results suggest that HDAC inhibition may represent a novel therapeutic modality for hypertrophy and heart failure.

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