An alpha-helix variant p.Arg156Pro in LMNA as a cause of hereditary dilated cardiomyopathy: genetics and bioinfomatics exploration.

LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted α-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the α-helix region mutation (p < 0.017). After screening the differentially expressed genes (DEGs) in both mice models and human patients in Gene Expression Omnibus database, we found the variation of α-helix-coding region in LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. Subsequently we constructed (TF)-mRNA-microRNA (miRNA) regulatory network and identified 7 key genes (FMOD, CYP1B1, CA3, F2RL1, HAPLIN1, SNAP91, and KANSL1) as potential biomarkers or therapeutic targets in LMNA-DCM patients.

[Effect of danshen injection on adult cardiac stem cell transplantation in myocardial infarction mice].

OBJECTIVE: To study the effect of combined use of Danshen Injection (Dl) on acute myocardial infarction (AMI) mice undergoing adult cardiac stem cell transplantation. METHODS: Thirty mice were randomly divided into 3 groups, 10 in each group, i.e., the high dose Dl group (at the daily dose of 5 g/kg) , the low dose Dl group (at the daily dose of 0. 5 g/kg), and the model control group. The AMI model was constructed by surgical ligation of the left anterior descending artery, and 2 x 10(6) -3 x 10(6) cardiac stem cells in vitro cultured were injected to the peripheral infracted zone immediately after successful modeling. All mice were administered with Dl by gastrogavage one week before myocardial infarction (Ml) and one week after Ml. Mice were sacrificed one week after Ml. Immunostaining was performed. The microvessel density (MVD) was detected using CD31 . The cell proliferation was detected using Ki67. The myocardial fibrosis degree was detected using Masson staining. The cell apoptosis of peripheral infracted zone was detected by TUNEL. Protein expressions of Akt and phospho-Akt were detected using Western blot. RESULTS: MVD and Ki67 positive cell number increased more in the high dose DI group than in the low dose DI group and the model control group (P < 0.05). The myocardial fibrosis degree and the cell apoptosis of peripheral infracted zone significantly decreased in the high dose DI group than in the low dose DI group and the model control group (P <0. 05). The phospho-Akt expression level significantly increased in the high dose DI group than in the low dose DI group and the model control group (P < 0.05). Compared with the model control group, the total Akt level significantly increased in the high dose and low dose DI groups (P < 0.05). But there was no statistical difference the high dose DI group and the low dose DI group (P > 0.05). CONCLUSION: Treating AMI by adult cardiac stem cell transplantation combined with DI could increase the MVD and cell proliferation, reduce cell apoptosis and fibrosis levels, thus improving the transplantation efficiency of adult cardiac stem cells.

Preliminary characterization of acute aortic dissection in the mainland of China.

OBJECTIVE: To explore the differences in the characteristics of acute aortic dissection (AAD) among less and more economically developed countries with various cultures and races. DATA SOURCES: Reports from the International Registry of Acute Aortic Dissection (IRAD) and the mainland of China (MC) were collected by searching the PubMed Database and the Chinese Journal Full-text Database from January 2000 to March 2009. STUDY SELECTION: Those reports from IRAD and MC containing larger numbers of cases and complete patients' information were selected, which focused on concrete issues of diagnosing or managing AAD were excluded if they were not able to reflect the overall characteristics of this condition. And the data from the article containing the largest number patients reported by the same medical center in MC were taken into statistics. RESULTS: AAD patients from MC were significantly younger than IRAD countries and the percentage of male patients in the Chinese group was higher than IRAD countries (80.7% vs. 68.6%, P < 0.001). Patients in MC were less likely to present with typical symptoms and signs except for any focal neurological deficits. Different from the IRAD group, Chinese patients were prone to undergo magnetic resonance imaging (MRI) to make the diagnosis of AAD (45.5% vs. 11.6%, P < 0.001). The in-hospital mortality was similar between 2 groups but only smaller proportion of AAD patients in MC underwent surgical or medical treatment. CONCLUSIONS: The general characteristics of AAD patients in MC were shown and differences in some clinical variables between MC and IRAD groups still existed.

[Ischemia-induced bone marrow-derived endothelial progenitor cells mobilization impairment in diabetic mice].

OBJECTIVE: To determine whether ischemia-induced bone marrow-derived EPCs mobilization is impaired in diabetic mice and the association with vascular endothelial growth factor (VEGF) release post ischemia. METHODS: C57Bl/6 mice were injected with 40 mg x kg(-1) x d(-1) streptozotocin for 5 days to induce diabetes and mice with fasting glucose > 10 mmol/L were included to DM group, control mice were injected with placebo. Two months later, hindlimb ischemia was induced by left femoral artery dissection and ligation. The ischemia was visualized by tetrazolium dye staining and pre-mortem angiography. The percentage of c-Kit(+)/Sca-1(+)/flk-1(+) early EPCs in peripheral blood mononuclear cells (PBMCs) was detected by flow cytometric analysis on days 0 (pre-ligation), 1, 3, 5, 7 and 14 days post-ligation. The plasma VEGF level was measured with a standardized ELISA-Kit. RESULTS: Circulating EPCs number was significantly lower in diabetic mice than that in control mice (0.60% +/- 0.03% vs. 0.95% +/- 0.09%, P < 0.001) and the plasma VEGF was undetectable in all animals before ligation Similar EPCs kinetics following induction of hindlimb ischemia were shown in both groups. However, EPCs mobilization was significantly impaired in diabetic mice compared with control mice within 3 days post ischemia (day 1: 1.16% +/- 0.20% vs. 1.80% +/- 0.32%, P < 0.05; day 3: 1.38% +/- 0.34% vs. 2.37% +/- 0.52%, P < 0.05). In parallel, plasma VEGF increase post ischemia was significantly less in diabetic mice than that in control mice (day 1: 73.1 pg/ml +/- 18.6 pg/ml vs. 128.5 pg/ml +/- 44.2 pg/ml, P < 0.05). CONCLUSION: Our data suggest that ischemia-induced bone marrow-derived EPCs mobilization is impaired in diabetic mice, which may be related to the insufficient release of plasma VEGF post ischemia.