T. brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes

Aims: African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. Methods and results: Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10–15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. Conclusion: These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression.

Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.福岡歯科大学2016年

Qualitative Improvement of a Coronary Plaque after Treatment with a Strong Statin : Observation using Virtual Histology Intravascular Ultrasound

Statins are used currently for treatment and prevention of coronary artery disease, but it is difficult to assess the therapeutics effects and patient responses to different statins. Virtual histology intravascular ultrasound (VH-IVUS) has been used to evaluate detailed quantitative changes in coronary plaques, and here we report a case in which marked qualitative improvement in a coronary plaque was observed using VH-IVUS after a change in treatment from a conventional statin to a strong statin

キュウセイ シンキンエン ガ ウタガワレ, ハツネツ ニヨリ ケンザイカ シタ ムショウコウセイ Brugadaショウコウグン ノ イチレイ

Brugada症候群は,重症不整脈を発症する症候群であるが,特異な心電図所見が明らかでなく診断に苦慮することがある.今回,発熱時心電図上ST上昇を認め,心筋炎を疑われ精査でBrugada症候群と診断した1例と,本邦で報告された発熱時顕在化した本症候群16例を検討した.症例は42歳男性,感冒症状とともに心電図所見でI.aV_R, aV_L, V_(1-4)のST上昇を認め急性心筋炎を疑われ入院した.心臓超音波検査でごく軽度心機能低下,心筋生検では異常なく,冠動脈造影では有意な狭窄はなかった.pilsicainide負荷でcoved型ST上昇を示し,電気生理学検査で容易に心室細動が誘発され,植込み型除細動器の植込み術が施行された.発熱時顕在化例で,高齢者群では高率に失神を発症した.Brugada症候群は発熱時顕在化することがあり,軽快により正常化するが,発熱と同時に失神や心室性不整脈が見られることがあり,十分な配慮が必要である.Brugada syndrome is a disease associated with severe arrhythmia but without specific ECG characteristics, which makes diagnosis difficult. We report the case of a patient with Brugada syndrome who had a ST segment elevation accompanied by fever, and we investigate 16 additional Japanese patients with Brugada syndrome that was recognized by fever. The patient was a 42-year-old man who showed ST segment elevation associated with cold symptoms and was admitted after diagnosis of myocarditis. Echocardiography exhibited slight cardiac dysfunction, but a myocardial biopsy showed no abnormalities and no significant stenosis was found in coronary angiography. After administration of pilsicainide, the patient showed covedtype ST segment elevation, and ventricular fibrillation was induced during an electrophysiological study ; therefore, an implantable cardioverter defibrillator (ICD) was installed. Among the patients with Brugada syndrome recognized by fever, many elderly patients showed syncope. In conclusion, Brugada syndrome frequently appears in fever and attention should be paid to elderly patients because they frequently develop fever and syncope simultaneously

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer

Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation

Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK-mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model