Defective autophagy in vascular smooth muscle cells enhances the healing of abdominal aortic aneurysm.

Autophagy is an evolutionarily conserved cellular catabolic process essential for cell homeostasis, and thus its failure is associated with several diseases. While autophagy has been reported to play a role in vascular smooth muscle cells (SMCs) in vascular disorders, its precise role in the pathogenesis of abdominal aortic aneurysm (AAA) has not yet been elucidated. In this study, we investigated the role of SMC autophagy in AAA formation. As a mouse model of AAA, we used control apolipoprotein E-deficient (apoeKO) mice and Atg7cKO (SMC-specific Atg7-deficient mice):apoeKO mice administered angiotensin II for 4 weeks. Intriguingly, Kaplan-Meier curves showed that the survival rates of Atg7cKO:apoeKO mice were significantly higher than those of apoeKO mice. The hematoma area in AAA of Atg7cKO:apoeKO mice was smaller than in apoeKO mice despite the lack of a significant difference in AAA incidence between the two groups. Furthermore, the amount of granulomatous tissues was significantly larger and the collagen-positive area within AAA was significantly larger in Atg7cKO:apoeKO mice than in apoeKO mice. In accordance with these findings, SMCs cultured from Atg7cKO mice showed increased expression of collagens, independent of angiotensin II action. Taken together, our data suggest that defective autophagy in SMCs elicits AAA healing that may underlie the better survival rate under dyslipidemia and angiotensin II infusion.

Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability.

Autophagy is considered as an evolutionarily conserved cellular catabolic process. Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. Recently, we and others demonstrated that defective autophagy in vascular smooth muscle cells (SMCs) promotes the progression of atherosclerosis. In this study, we investigated the role of autophagy in SMCs on plaque instability in vivo. We generated mice with a defect atg7in which is an essential gene for autophagy, in SMCs by crossing Atg7f/f mice with transgelin (Tagln) Cre+/0 mice (Atg7cKO). Then, Atg7cKO and apolipoprotein E (apoe)-deficient (apoeKO) mice were crossed to generate Atg7cKO:apoeKO mice. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice and their controls (apoeKO mice) at the age of 10 weeks. At 5 weeks after surgery, the percentage of cross-sectional stenosis area in the operated common carotid artery of Atg7cKO:apoeKO mice was significantly higher than that in apoeKO mice. In addition, thrombus, which was not observed in apoeKO mice, was frequently found in Atg7cKO:apoeKO mice. Furthermore, the number of Berlin blue staining-positive areas, which indicated intraplaque hemorrhage, was significantly higher in Atg7cKO:apoeKO mice than in control apoeKO mice. Taken together, our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.

Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis.

Macroautophagy/autophagy is considered as an evolutionarily conserved cellular catabolic process. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis. SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) showed reduced serum-induced cell growth, increased cell death, and decreased cell proliferation rate. Furthermore, 7-ketocholestrerol enhanced apoptosis and the expression of CCL2 (chemokine [C-C motif] ligand 2) with the activation of TRP53, the mouse ortholog of human and rat TP53, in SMCs from Atg7cKO mice. In addition, Atg7cKO mice crossed with Apoe (apolipoprotein E)-deficient mice (apoeKO; Atg7cKO:apoeKO) showed reduced medial cellularity and increased TUNEL-positive cells in the descending aorta at 10 weeks of age. Intriguingly, Atg7cKO: apoeKO mice fed a Western diet containing 1.25% cholesterol for 14 weeks showed a reduced survival rate. Autopsy of the mice demonstrated the presence of aortic rupture. Analysis of the descending aorta in Atg7cKO:apoeKO mice showed increased plaque area, increased TUNEL-positive area, decreased SMC-positive area, accumulation of macrophages in the media, and adventitia and perivascular tissue, increased CCL2 expression in SMCs in the vascular wall, medial disruption, and aneurysm formation. In conclusion, our data suggest that defective autophagy in SMCs enhances atherosclerotic changes with outward arterial remodeling.

Relationship between the degree of endoscopic atrophy of the gastric mucosa and carcinogenic risk.

BACKGROUND: The relationship between Helicobacter pylori infection and gastric cancer has been demonstrated, and the risk of gastric cancer occurrence is known to increase with the progression of atrophic changes associated with chronic gastritis. Endoscopic evaluation of the degree and extent of atrophy of the gastric mucosa is a simple and very important means of identifying a group at high risk for gastric cancer. This study aimed to clarify the carcinogenic risk in relation to the degree of atrophy. METHODS: A total of 27,777 patients (272 with early gastric cancer and 135 with advanced gastric cancer) were included in this study. Endoscopically evaluated atrophy of the gastric mucosa was classified as C-0 to O-3 according to the Kimura and Takemoto classification system. RESULTS: The cancer detection rate in relation to the degree of gastric mucosal atrophy was 0.04% (2/4,183 patients) for C-0, 0% (0/4,506) for C-1, 0.25% (9/3,660) for C-2, 0.71% (21/2,960) for C-3, 1.32% (75/5,684) for O-1, 3.70% (140/3,780) for O-2 and 5.33% (160/3,004) for O-3. As to the proportions of differentiated and undifferentiated cancers, the latter were relatively frequent in the C-0 to C-2 groups, but differentiated cancers became predominant as atrophy progressed. On the other hand, the number of both differentiated and undifferentiated cancers detected increased as gastric mucosal atrophy progressed. In addition, open-type atrophy was found in 29 (96.7%) of 30 patients with synchronous multiple gastric cancers and in all 20 patients with metachronous multiple gastric cancers. CONCLUSION: Endoscopic evaluation of gastric mucosal atrophy can provide a simple and reliable predictive index for both current and future carcinogenic risk.

A case of adult-onset Still's disease complicated by thrombotic thrombocytopenic purpura with retinal microangiopathy and rapidly fatal cerebral edema.

We present a patient who had adult-onset Still's disease (AOSD) complicated by thrombotic thrombocytopenic purpura (TTP) that resulted in retinal microangiopathy and rapidly fatal cerebral edema. The patient was a 37-year-old male who developed fever, eruption, arthritis and hepatic dysfunction, that, based on close examination, was diagnosed as AOSD. Despite treatment with corticosteroids, the patient developed acute visual field defect, neurological deterioration including convulsions and impaired consciousness, as well as acute renal failure that ultimately resulted in death. Pathological examination of autopsy specimens revealed multiple fibrin thrombi disseminated in small vessels of the brain and kidney, which was consistent with TTP, along with marked cerebral edema. Although TTP has rarely been reported in association with AOSD, awareness of the possible coexistence of these two diseases is important for diagnosis and treatment.

Behçet's disease initially presenting with meningitis and sudden hearing loss.

We report a patient with neuro Behçet's disease (BD) initially presenting with meningitis and severe hearing loss. A 51-year-old man with no noteworthy past history was hospitalized for evaluation of non-pulsating headache and high fever. Lumbar puncture on admission only showed slight pleocytosis (6 /microL, monomorphonuclear cells predominantly) but no evidence of meningitis. However, after admission, he continued to have a fever of over 38 degrees, and he developed painful oral aphthous ulcer and pseudofolliculitis on the upper limbs and trunk. Prior to admission he had often experienced oral ulceration and had bought commercially available mouthwash for prophylaxis. Subsequently, genital ulceration appeared. A small ulcer was observed at the blood collection site, leading to the diagnosis of BD. On the seventh hospital day, the patient developed sudden hearing loss, which was diagnosed as severe sensorineural hearing loss. Lumbar puncture was performed again. Cerebrospinal fluid (CSF) analysis showed mild pleocytosis (60 /microL, predominantly monomorphonuclear cells), with high CSF IL-6 levels. Neither edematous change nor atrophy of the brainstem was noted and there were no other abnormal findings on the brain MRI/MRA. Auditory brainstem response was normal, suggesting that the patient had developed hearing loss due to peripheral neuropathy. We speculate that the hearing loss was likely due to vasculitis associated with BD. This case is considered to be a rare case of Behçet's disease caused by severe hearing loss and meningitis.