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We aimed to describe a technique for approaching the common femoral artery (CFA) in cases where doing so is difficult owing to an occluded lesion caused by a previously implanted stent. A 72-year-old woman had severe stenotic lesions in both iliac arteries that required an approach via the bilateral femoral arteries. The right CFA had a previously implanted stent and a completely occluded lesion that extended from the superficial femoral artery (SFA). A 20G needle was inserted through the proximal SFA, and the needle tip was advanced into the CFA stent and passed through the occluded lesion using a microcatheter and guide wire (GW). This allowed us to insert a guide catheter via the GW into the occluded lesion. No complications, such as bleeding, were observed after the procedure. When the CFA is occluded by a stent, an ascending approach through the proximal SFA is a viable treatment option. Learning objective: An occluded lesion due to a previously implanted stent makes approaching the common femoral artery difficult. Hence, alternative approaches are needed. In this regard, an approach via the proximal superficial femoral artery may prove useful.
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Large-scale multicenter studies demonstrating the safety and effectiveness of transradial iliac artery stenting are lacking. We evaluated the data from a multicenter database in Japan. Transradial iliac artery stenting was performed on 115 lesions in 105 patients. The approach site was determined at the discretion of the operator. Patients with scheduled multiple sheath insertions for the bidirectional approach were excluded. Clinical data were retrospectively analyzed. The average age of this cohort was 71.1 ± 8.3 years. Eighty-six patients (81.9%) were male. Diabetes mellitus, hypertension, dyslipidemia, and smoking habit were present in 39 (37.1%), 84 (80.0%), 69 (65.7%), and 78 patients (74.3%), respectively. Rutherford classifications 1, 2, 3, 4, and 5 comprised 40 (34.8%), 42 (36.5%), 28 (24.3%), 3 (2.6%), and 2 (1.7%) lesions, respectively, while Trans-Atlantic Inter-Society Consensus II classifications A, B, C, and D comprised 74 (64.3%), 21 (18.3%), 15 (13.0%), and 5 (4.3%), respectively. Twenty-seven lesions (23.5%) had chronic total occlusion. All lesions were successfully treated with 141 stents. Four patients (3.8%) required additional puncture of the common femoral artery for successful stent implantation. The ankle-brachial index significantly improved from 0.65 ± 0.17 to 0.95 ± 0.15 (P < 0.0001). None of the patients experienced any procedural or access site-related complications. Asymptomatic radial artery occlusion was observed in three cases (2.9%) after the procedure. There were no target lesion revascularizations or complications at 1 month. Compared to the traditional transfemoral approach, transradial iliac artery stenting is safe and feasible without any specific complications in carefully selected patients.
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The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/µL), very high CD8-positive T-cell levels (58.9%; 5,751/µL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/µL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future.
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Infecciones por Citomegalovirus , Síndrome de DiGeorge , Cardiopatías Congénitas , Atresia Pulmonar , Lactante , Humanos , Recién Nacido , Síndrome de DiGeorge/complicaciones , Recien Nacido Prematuro , Infecciones por Citomegalovirus/complicacionesRESUMEN
BACKGROUND: Acute aortic dissection (AAD) has high morbidity and a high fatality rate for a cardiovascular disease. Recent studies suggested that the incidence of AAD is increasing. However, the actual incidence and mortality rates of AAD are not well known. This study investigated the current epidemiology of AAD within the Yatsushiro medical jurisdictional area.MethodsâandâResults: A population-based review of patients with AAD was performed in a geographically well-defined area. Data were collected retrospectively from January 2011 to December 2020 for a total of 196 patients with AAD (Stanford Type A, n=126 [64.3%]; Stanford Type B, n=70 [35.7%]). The mean patient age was 74.3 years, and 55.6% (109/196) were women. The crude and age-standardized incidence rates of AAD in our medical jurisdictional area were 13.6 and 11.4 per 100,000 inhabitants per year, respectively. The crude and age-standardized 30-day mortality rates of AAD were 4.9 and 4.0 per 100,000 inhabitants per year, respectively. There were upward tendencies for both the incidence and 30-day mortality rate of AAD with age, with both being significantly higher in patients aged ≥85 years (P<0.001). CONCLUSIONS: This population-based study detected a higher incidence of AAD than previous studies, but reported a lower incidence of AAD in men than in women. Increasing age was associated with an increased incidence and mortality rate of AAD.
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Disección Aórtica , Masculino , Humanos , Femenino , Anciano de 80 o más Años , Anciano , Incidencia , Estudios Retrospectivos , Disección Aórtica/epidemiología , Enfermedad Aguda , Factores de RiesgoRESUMEN
BACKGROUND: Mitral-aortic intervalvular fibrosa (MAIVF) is a fibrous region connecting the anterior mitral leaflet (AML) and aortic valve. Pseudoaneurysm of the MAIVF is a rare condition that has been reported as a sequela of infective endocarditis (IE) and surgical trauma. Here, we report a case of a ruptured pseudoaneurysm of the MAIVF, along with some literature reviews. CASE PRESENTATION: A 65-year-old man diagnosed with moderate aortic regurgitation five years previously had a fever of unknown origin. He suddenly developed headache and apraxia and was transported to our hospital. He was diagnosed with intracranial hemorrhage and admitted. One week after admission, echocardiography revealed aorto-mitral discontinuity and protrusion with severe regurgitant flow from left ventricular outflow tract to the left atrium. The AML was suspected to have ruptured. However, intraoperatively, the AML structure was preserved. A ruptured pseudoaneurysm of the MAIVF was also observed. Therefore, we successfully performed pseudoaneurysm repair using a bovine pericardial patch, aortic valve replacement, and mitral annuloplasty. CONCLUSIONS: P-MAIVF is a rare but potentially life-threatening complication of IE, for which timely diagnosis and prompt appropriate therapeutic intervention are required. In the present case, although neither obvious active IE nor history of previous IE could be identified, healed IE was considered based on the clinical course. The patient had intracranial hemorrhage (ICH) with well-controlled heart failure and underwent elective surgical repair more than one month after the onset of ICH, while the clinical course after the surgical procedure was uneventful.
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A 76-year-old man undergoing hemodialysis complained of pain and discoloration of his right finger. The hemodialysis arteriovenous fistula was in the right upper extremity. Ultrasonography showed right subclavian artery occlusion. The lesion could not be approached from the lower extremity and olecranon artery. Thus, we performed the procedure after exposing the proximal brachial artery. We were able to recanalize the subclavian artery and restore blood flow to the right upper extremity. When the lesion is on the side of the arteriovenous fistula and approaching from the lower extremity is difficult, exposure of the proximal brachial artery can be considered.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Masculino , Humanos , Anciano , Arteria Subclavia/diagnóstico por imagen , Arteria Subclavia/cirugía , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/cirugía , Extremidad Superior , Diálisis Renal/efectos adversos , Fístula Arteriovenosa/diagnóstico por imagen , Fístula Arteriovenosa/etiología , Fístula Arteriovenosa/cirugíaRESUMEN
Background: The severity of peripheral artery disease (PAD) is usually diagnosed by physiological assessments, such as the ankle brachial index (ABI) or peak systolic velocity (PSV) on ultrasonography. We examined peripheral fractional flow reserve (pFFR: distal mean pressure divided by proximal mean pressure) measured by a pressure wire and pressure gradient to diagnose PAD patients who do not have lowered ABI or high PSV on ultrasonography. Case summary: An 84-year-old woman with intermittent claudication in her left leg had severe calcification in the left common femoral artery (CFA) on angiography. The exercise-stress ABI of pre-endovascular therapy (EVT) was 1.05/0.98. In addition, the PSV of the left CFA on ultrasonography was 230â cm/s. However, the pFFR using papaverine and alprostadil in the left CFA was 0.86, which was a significant score. In addition, the systolic pressure gradient between the distal and proximal regions was >20â mmHg. We performed EVT for the lesion, and the pFFR improved to 0.96. The systolic pressure gradient was only 1â mmHg at the lesion. Discussion: Symptomatic PAD patients whose ABI or PSV on ultrasonography is insufficient for EVT could be diagnosed with ischaemia using a pressure gradient and pFFR.
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PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.
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BACKGROUND: In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has received increasing attention; however, the epidemiology of ATTR-CM in Japan is not yet understood. In the Kumamoto Cardiac Amyloid Survey, we evaluated the current incidence, clinical characteristics, diagnostic approaches, and treatment strategies for ATTR-CM and compared tafamidis-prescription hospitals with regional hospitals. METHODS: We conducted a retrospective multicenter observational cohort study. The registry included patients with ATTR-CM diagnosed in two tafamidis-prescription hospital institutes [Japanese Circulation Society (JCS)-certified facilities] and 15 regional cardiovascular facilities in Kumamoto between January 2018 and December 2020. RESULTS: In total, 174 patients were diagnosed with ATTR-CM. The incidence of ATTR-CM was estimated to be approximately 1 per 10,000 person-years in the elderly population (>65 years old) in Kumamoto. Compared with that in the JCS-certified facilities cohort (n=115), age at diagnosis was significantly older (84.5 ± 5.6 vs. 77.5 ± 6.3 years old; p<0.01) in the regional hospitals cohort (n=59). Histological (25% vs. 81%; p<0.01) and genetic diagnosis (7% vs. 82%) were also less frequently performed. Probable (as indicated by positive bone scintigraphy findings with confirmation of monoclonal protein absence) and possible (as indicated by positive bone scintigraphy findings without confirmation of monoclonal protein absence) ATTR-CM accounted for the majority of cases (75% vs. 19%; p<0.01) in the regional hospitals cohort compared to the JCS-certified facilities cohort. There were no cases of hereditary ATTR-CM among the patients who underwent TTR genetic testing (n=98). CONCLUSIONS: We confirmed the incidence of ATTR-CM in Kumamoto and the diagnostic approach used in patients with ATTR-CM. Further prospective studies with a larger sample are needed to validate our results and to further shed light on the epidemiology of ATTR-CM in Japan.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/genética , Humanos , Incidencia , Prealbúmina/genética , Estudios ProspectivosRESUMEN
A 59-year-old female was brought to our emergency room with severe chest pain. Based on the electrocardiogram (ECG) and echocardiography, an acute coronary syndrome (ACS) was suspected. Her initial ECG showed ST elevation in the inferior leads (II, III, and aVF), which had progressed to involve the anterior leads (V2-V4) by the time she was shifted to the catheterization room. A coronary angiogram revealed total occlusion of the mid-left anterior descending (LAD) artery and a filling defect of the distal right coronary artery. Although we had emergently treated her using thrombus aspiration following stent implantation, lots of thrombi re-formed on the stent. We surmised her ACS was primarily caused by thrombus formation due to polycythemia vera (PV) based on the presence of increased blood consistency on admission. We performed repetitive long-inflation using a perfusion balloon and repeated thrombus aspiration. Finally, she was diagnosed as an untreated case of PV as a result of detailed blood investigations. Thereafter, we successfully treated her using the combination of dual antiplatelet therapy and direct oral anticoagulant therapy. Our experience highlights the importance of an urgent identification of PV. Effective management strategies should be successfully implemented in such patients as soon as possible.
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OBJECTIVES: There have been limited data regarding the prediction of cardiac benefits after renal artery stenting for patients with atherosclerotic renal artery disease (ARAD). The aim of this multicentre retrospective study was to identify clinical or echocardiographic factors associated with improvements of cardiac symptoms after renal artery stenting. METHODS: We enrolled 58 patients with de novo ARAD undergoing successful renal artery stenting for heart failure, angina or both between January 2000 and August 2015 at 13 hospitals. RESULTS: Improvement of cardiac symptoms was observed in 86.2% of patients during a mean follow-up of 6.0±2.7 months. Responders demonstrated significantly lower New York Heart Association functional class, higher estimated glomerular filtration rate, lower serum creatinine and lower interventricular septal wall thickness (IVS), lower left ventricular mass index, lower left atrial dimension and lower E-velocity than non-responders. Backward stepwise multivariate analysis identified IVS as an independent predictor of improvement of cardiac symptoms (OR 0.451, 95% CI 0.209 to 0.976; p=0.043). According to receiver operating characteristic curve analysis, an IVS cut-off of 11.9 mm provided the best predictive value, with sensitivity of 71.4%, specificity of 75.5% and accuracy of 73.5%. The positive predictive value was 74.5% and the negative predictive value was 72.5%. CONCLUSIONS: This multicentre retrospective study shows that the echocardiographic index of IVS is an independent predictor for improvement of cardiac symptoms after renal artery stenting.
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The accumulation of abnormal proteins is a common characteristic of neurodegenerative diseases. This accumulation reflects a severe disturbance of cellular homeostasis in pathogenic protein clearance. Here, we demonstrated that the activation of the two major proteolytic machineries, the molecular chaperone-ubiquitin proteasome system (UPS) and the autophagy system, were simultaneously enhanced by paeoniflorin (PF), a major component of Paeonia plants, and exerted therapeutic effects in models of spinal and bulbar muscular atrophy (SBMA). PF significantly increased the expression of nuclear factor-YA (NF-YA), which strongly upregulated the molecules involved in the proteolytic machinery [molecular chaperones, carboxyl terminus of Hsc70-interacting protein and transcription factor EB], which thus mitigated the behavioral and pathological impairments in an SBMA mouse model through the upregulation of pathogenic androgen receptor protein clearance in motor neurons and muscles. These findings demonstrated that PF is able to enhance both the UPS and autophagy systems by upregulating the expression of NF-YA, which promotes therapeutic effects in an SBMA model.
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Glucósidos/uso terapéutico , Monoterpenos/uso terapéutico , Receptores Androgénicos/genética , Animales , Línea Celular , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Supervivencia Celular/efectos de la radiación , Inmunohistoquímica , Ratones , Atrofia Muscular Espinal , Proteolisis/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR.
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Cuerpos de Inclusión/patología , Trastornos Musculares Atróficos/genética , Trastornos Musculares Atróficos/patología , Mutación/genética , Receptores Androgénicos/genética , Factores de Transcripción/metabolismo , Anciano , Animales , Autofagia/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Trastornos Musculares Atróficos/fisiopatología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Células PC12 , Péptidos/genética , Ratas , Receptores Androgénicos/metabolismo , Factor de Transcripción TFIIH , Factores de Transcripción/deficiencia , TransfecciónRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR-associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high-molecular-weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70.
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Genisteína/farmacología , Enfermedad de la Neurona Motora/inducido químicamente , Enfermedad de la Neurona Motora/prevención & control , Fármacos Neuroprotectores , Péptidos/fisiología , Animales , Conducta Animal/efectos de los fármacos , Células Cultivadas , ADN Complementario/biosíntesis , ADN Complementario/genética , Inmunohistoquímica , Luciferasas/metabolismo , Ratones , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Músculo Esquelético/patología , Trastornos Musculares Atróficos/genética , Trastornos Musculares Atróficos/patología , Coactivadores de Receptor Nuclear/genética , Coactivadores de Receptor Nuclear/fisiología , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/genética , Médula Espinal/patologíaRESUMEN
A crucial feature of adult-onset neurodegenerative diseases is accumulation of abnormal protein in specific brain regions, although the mechanism underlying this pathological selectivity remains unclear. Heat shock factor-1 is a transcriptional regulator of heat shock proteins, molecular chaperones that abrogate neurodegeneration by refolding and solubilizing pathogenic proteins. Here we show that heat shock factor-1 expression levels are associated with the accumulation of pathogenic androgen receptor in spinal and bulbar muscular atrophy, a polyglutamine-induced neurodegenerative disease. In heterozygous heat shock factor-1-knockout spinal and bulbar muscular atrophy mice, abnormal androgen receptor accumulates in the cerebral visual cortex, liver and pituitary, which are not affected in their genetically unmodified counterparts. The depletion of heat shock factor-1 also expands the distribution of pathogenic androgen receptor accumulation in other neuronal regions. Furthermore, lentiviral-mediated delivery of heat shock factor-1 into the brain of spinal and bulbar muscular atrophy mice topically suppresses the pathogenic androgen receptor accumulation and neuronal atrophy. These results suggest that heat shock factor-1 influences the pathological lesion selectivity in spinal and bulbar muscular atrophy.
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Proteínas de Unión al ADN/metabolismo , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Péptidos/toxicidad , Factores de Transcripción/metabolismo , Anciano , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Células HEK293 , Factores de Transcripción del Choque Térmico , Proteínas de Choque Térmico/metabolismo , Heterocigoto , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Corteza Motora/efectos de los fármacos , Corteza Motora/metabolismo , Corteza Motora/patología , Trastornos Musculares Atróficos/metabolismo , Trastornos Musculares Atróficos/patología , Proteínas Mutantes/metabolismo , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neostriado/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Especificidad de Órganos/efectos de los fármacos , Hipófisis/metabolismo , Receptores Androgénicos/metabolismo , TransgenesRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.
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Calcitonina/metabolismo , Trastornos Musculares Atróficos/genética , Péptidos , Piperidinas/farmacología , Precursores de Proteínas/metabolismo , Receptores Androgénicos/genética , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Expansión de Repetición de Trinucleótido , Triptaminas/farmacología , Animales , Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina , Supervivencia Celular , Células Cultivadas , Fosfatasa 1 de Especificidad Dual/biosíntesis , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Enfermedad de la Neurona Motora/genética , Trastornos Musculares Atróficos/metabolismo , Trastornos Musculares Atróficos/patología , Precursores de Proteínas/genética , Interferencia de ARN , ARN Interferente Pequeño , Receptores Androgénicos/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) tract of the androgen receptor (AR-polyQ). Characteristics of SBMA include proximal muscular atrophy, weakness, contraction fasciculation and bulbar involvement. MicroRNAs (miRNAs) are a diverse class of highly conserved small RNA molecules that function as crucial regulators of gene expression in animals and plants. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention. Here we describe a novel therapeutic approach using the adeno-associated virus (AAV) vectormediated delivery of a specific miRNA for SBMA. We found that miR-196a enhanced the decay of the AR mRNA by silencing CUGBP, Elav-like family member 2 (CELF2). CELF2 directly acted on AR mRNA and enhanced the stability of AR mRNA. Furthermore, we found that the early intervention of miR-196a delivered by an AAV vector ameliorated the SBMA phenotypes in a mouse model. Our results establish the proof of principle that disease-specific miRNA delivery could be useful in neurodegenerative diseases.
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Dependovirus/genética , Silenciador del Gen , Terapia Genética , MicroARNs/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/prevención & control , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN/genética , Anciano , Animales , Secuencia de Bases , Proteínas CELF , Exones/genética , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones , MicroARNs/química , MicroARNs/metabolismo , MicroARNs/uso terapéutico , Persona de Mediana Edad , Datos de Secuencia Molecular , Atrofia Muscular Espinal/patología , Proteínas Mutantes/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Conformación de Ácido Nucleico , Fenotipo , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-beta signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-beta signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-beta receptor type II (TbetaRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TbetaRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-beta due to the transcriptional dysregulation of TbetaRII is associated with polyglutamine-induced motor neuron damage in SBMA.