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Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

ABSTRACT: Cardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function in CH is still unclear. Herein, we investigated the roles of MTMR14 in CH. We show that MTMR14 expression was increased in hypertrophic mouse hearts. Mice deficient in heart MTMR14 exhibited an aggravated aortic-banding (AB)-induced CH phenotype. In contrast, MTMR14 overexpression prevented pressure overload-induced hypertrophy. At the molecular level, prevention of CH in the absence of MTMR14 involved elevations in Akt pathway components, which are key elements that regulate apoptosis and cell proliferation. These results demonstrate that MTMR14 is a new molecular target for the treatment of CH.

SUBMITTER: Zhang JL

PROVIDER: S-EPMC7033093 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

Zhang Jie-Lei JL Zhang Dian-Hong DH Li Ya-Peng YP Wu Lei-Ming LM Liang Cui C Yao Rui R Wang Zheng Z Feng Sheng-Dong SD Wang Zhong-Min ZM Zhang Yan-Zhou YZ

Cell death & disease 20200220 2

Cardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function ...[more]

PMID: 32080168

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Project description:Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8?mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.

Project description:BACKGROUND:The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a proinflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14(-/-) mice that lack MRP-8/14 complexes. METHODS AND RESULTS:We examined parenchymal rejection after major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP-14(-/-) recipients. Allograft survival averaged 5.9±2.9 weeks (n=10) in MRP-14(-/-) recipients compared with >12 weeks (n=15; P<0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP-14(-/-) recipients had significantly higher parenchymal rejection scores (2.8±0.8; n=8) than did WT recipients (0.8±0.8; n=12; P<0.0001). Compared with WT recipients, allografts in MRP-14(-/-) recipients had significantly increased T-cell and macrophage infiltration and increased mRNA levels of interferon-? and interferon-?-associated chemokines (CXCL9, CXCL10, and CXCL11), interleukin-6, and interleukin-17 with significantly higher levels of Th17 cells. MRP-14(-/-) recipients also had significantly more lymphocytes in the adjacent para-aortic lymph nodes than did WT recipients (cells per lymph node: 23.7±0.7×10(5) for MRP-14(-/-) versus 6.0±0.2×10(5) for WT; P<0.0001). The dendritic cells (DCs) of the MRP-14(-/-) recipients of bm12 hearts expressed significantly higher levels of the costimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions with allo-endothelial cell-primed MRP-14(-/-) DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP-14(-/-) DCs augmented proliferation of OT-II (ovalbumin-specific T cell receptor transgenic) CD4(+) T cells with increased interleukin-2 and interferon-? production. Cardiac allografts of B6 major histocompatibility complex class II(-/-) hosts and of B6 WT hosts receiving MRP-14(-/-) DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection compared with WT DCs from transferred recipient allografts. Bone marrow-derived MRP-14(-/-) DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared with controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression. CONCLUSIONS:Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology.

Dataset Information

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

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Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

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