Journal of molecular and cellular cardiology plus最新文献

Background

Septic cardiomyopathy is a common complication of septic shock and organ dysfunction. ITCH is a HECT (homologous to the E6-AP carboxyl-terminus)-type ubiquitin E3 ligase that plays a critical role in inflammatory suppression. Herein, we focused on the interaction between ITCH and key regulators of nuclear factor-κB (NF-κB), such as tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β activated kinase 1 (TAK1), and examined the impact of ITCH on the development of septic cardiomyopathy.

Methods and results

In H9C2 cardiomyocytes, ITCH protein expression decreased in response to lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα). The protein interactions of ITCH with TRAF6 and TAK1 were confirmed by immunoprecipitation in vitro and in vivo. Based on overexpression and knockdown studies of ITCH in H9C2 cardiomyocytes, ITCH regulates the phosphorylation of NF-κB and subsequent interleukin 6 (IL-6) expression in response to LPS and TNFα stimulation. LPS was intraperitoneally injected into transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type (WT) mice. Compared with WT mice, phosphorylation of NF-κB and subsequent IL-6 expression were inhibited in ITCH-Tg mice. Cardiac systolic dysfunction after LPS administration was ameliorated in ITCH-Tg mice, and the survival rate was higher in ITCH-Tg mice than in WT mice.

Conclusion

ITCH interacts with TRAF6 and TAK1 in cardiomyocytes and improves cardiac function and survival rates in septic cardiomyopathy by suppressing the NF-κB pathway.

Objective

The purpose of this study was to examine the effect of 12 weeks of moderate intensity aerobic exercise on echocardiographic and cardiorespiratory fitness (CRF) parameters, lymphocyte estrogen receptor alpha (ERα) gene expression and sex hormones (17β-estradiol and progesterone) in overweight/obese postmenopausal women (OPMW).

Methods

Twenty-seven sedentary OPMW aged 45 to 65 years old were randomly assigned to exercise (EX, n = 14) and control (C, n = 13) groups. The EX group performed warm up-walking/jogging moderate intensity aerobic exercise program- recovery (60 min/day, 3 days/week at 70 % of maximal heart rate reserve for 12 weeks) while the C group participated in no intervention and maintained their daily physical activity level, sedentary normal lifestyle and dietary habits during 12-week. The lymphocyte ERα gene expression, serum levels of 17β-estradiol and progesterone, and CRF & echocardiographic parameters were measured at baseline and week-12.

Results

After 12-week, the increase in ERα gene expression (p = 0.009, estimate of effect size/Eta = 28.2 %), VO_2max (p = 0.001, Eta = 53.4 %), walking-jogging time to exhaustion (WJTE) (p = 0.001, Eta = 55.1 %), metabolic equivalent of task (METs) (p = 0.001, Eta = 97.9 %), left ventricular ejection fraction (LVEF) (p = 0.001, Eta = 53.6 %), cardiac output (Q) (p = 0.036, Eta = 22.3 %), and cardiac index (p = 0.030, Eta = 22.5 %) were significantly higher in the EX group compared to the C group, whereas body fat (p = 0.023, Eta = 25.7 %), left ventricular end-systolic diameter (LVESD) (p = 0.013, Eta = 28.3 %), and mitral E-wave deceleration time (E-wave D time) (p = 0.007, Eta = 32.1 %) were significantly decreased.

Conclusions

The results suggested that moderate intensity aerobic exercise can be improved cardiac function such as LVEF, Q, cardiac index, LVESD, and E-wave D time, CRF, ERα-mRNA gene expression as well as maintained sex hormones among sedentary OPMW during menopause, as these positive cellular and molecular or physiological adaptations may be signs of cardioprotective effects by aerobic exercise.

Left ventricular hypertrophy, characterized by hypertrophy of individual cardiomyocytes, is an adaptive response to an increased cardiac workload that eventually leads to heart failure. Previous studies using neonatal rat ventricular myocytes (NRVMs) and animal models have revealed several genes and signaling pathways associated with hypertrophy and mechanical load. However, these models are not directly applicable to humans. Here, we studied the effect of cyclic mechanical stretch on gene expression of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using RNA sequencing. hiPSC-CMs showed distinct hypertrophic changes in gene expression at the level of individual genes and in biological processes. We also identified several differentially expressed genes that have not been previously associated with cardiomyocyte hypertrophy and thus serve as attractive targets for future studies. When compared to previously published data attained from stretched NRVMs and human embryonic stem cell-derived cardiomyocytes, hiPSC-CMs displayed a smaller number of changes in gene expression, but the differentially expressed genes revealed more pronounced enrichment of hypertrophy-related biological processes and pathways. Overall, these results establish hiPSC-CMs as a valuable in vitro model for studying human cardiomyocyte hypertrophy.

The calcium sensitivity hypothesis helps explain the development of different forms of cardiomyopathy: increased sensitivity to calcium in cardiac sarcomeres leads to hypertrophic cardiomyopathy (HCM) and decreased sensitivity results in dilated cardiomyopathy (DCM). This hypothesis has driven the development of next generation drugs targeting sarcomere proteins to correct the amount of force generated as a result of changes in calcium sensitivity (e.g. mavacamten decreases cardiac myosin activity to treat HCM). Characterization of variants of cardiac actin (ACTC) found in patients with HCM or DCM has generally supported the calcium sensitivity hypothesis. Of interest are two different substitution mutations at R312 on ACTC: R312H leads to DCM, while R312C was found in patients with HCM. To determine how changes in the same codon on the same gene lead to different disease phenotypes, we characterized recombinant R312H- and R312C-ACTC variant proteins. Both variants exhibited the same change in calcium sensitivity, suggesting that a factor other than calcium sensitivity is responsible for disease differentiation. We observed a gradient of increased residual myosin activity with R312-ACTC variant proteins under relaxing conditions which may trigger different disease development. Our findings suggest that factors other than calcium sensitivity may contribute to cardiomyopathy development and should be considered when planning treatments.

The potential use of the D2.mdx mouse (the mdx mutation on the DBA/2J genetic background) as a preclinical model of the cardiac aspects of Duchenne muscular dystrophy (DMD) has been criticized based on speculation that the DBA/2J genetic background displays an inherent hypertrophic cardiomyopathy (HCM) phenotype. Accordingly, the goal of the current study was to further examine the cardiac status of this mouse strain over a 12-month period to determine if observable signs of HCM develop, including histopathology and pathological enlargement of the myocardium. Previous reports have documented heightened TGFβ signaling in the DBA2/J striated muscles, as compared to the C57 background, which, as expected, is manifested as increased cardiomyocyte size, wall thickness, and heart mass as compared to the C57 background. While normalized heart mass is larger in the DBA/2J mice, compared to age-matched C57/BL10 mice, both strains similarly increase in size from 4 to 12 months of age. We also report that DBA/2J mice contain equivalent amounts of left ventricular collagen as healthy canine and human samples. In a longitudinal echocardiography study, neither sedentary nor exercised DBA/2J mice demonstrated left ventricular wall thickening or cardiac functional deficits. In summary, we find no evidence of HCM, nor any other cardiac pathology, and thus propose that it is an appropriate background strain for genetic modeling of cardiac diseases, including the cardiomyopathy associated with DMD.