Causal associations between chronic viral hepatitis and psychiatric disorders: a Mendelian randomization study.

Background: There may be an interaction between viral hepatitis and psychiatric disorders during disease progression. Herein, we conducted Mendelian randomization (MR) to explore the causal associations and mediators between viral hepatitis and psychiatric disorders. Methods: Genome-wide association studies summary data for viral hepatitis [including chronic hepatitis B (CHB) and chronic hepatitis C (CHC)] and psychiatric disorders (including depression, anxiety, schizophrenia, obsessive-compulsive disorder, bipolar disorder, and post-traumatic stress disorder) were obtained. Two-sample MR was performed to assess the causal associations between viral hepatitis and psychiatric disorders. Further, a mediation analysis was conducted to evaluate the potential mediators. Inverse-variance weighted, MR-Egger, and weighted median were used as the main methods, while a sensitivity analysis was performed to evaluate pleiotropy and heterogeneity. Results: There was no causal effect of CHB/CHC on psychiatric disorders, as well as psychiatric disorders on CHB. However, schizophrenia presented a causal effect on increased CHC risk [odds ratio (OR)=1.378, 95%CI: 1.012-1.876]. Further, a mediation analysis identified coffee consumption and body mass index as mediators in the effect of schizophrenia on CHC, mediating 3.75% (95%CI: 0.76%-7.04%) and 0.94% (95%CI: 0.00%-1.70%) proportion, respectively. Conclusion: We revealed that schizophrenia patients faced a high risk of CHC, and insufficient coffee consumption and underweight could mediate the causal effect of schizophrenia on CHC. The prevention of hepatitis C might be a beneficial strategy for patients with schizophrenia. The right amount of nutrition supplements and coffee consumption might be part of a beneficial lifestyle in preventing the high CHC risk in patients with schizophrenia.

Type III Transforming Growth Factor-ß Receptor Drives Cardiac Hypertrophy Through ß-Arrestin2-Dependent Activation of Calmodulin-Dependent Protein Kinase II.

The role of type III transforming growth factor-ß receptor (TßRIII) in the pathogenesis of heart diseases remains largely unclear. Here, we investigated the functional role and molecular mechanisms of TßRIII in the development of myocardial hypertrophy. Western blot and quantitative real time-polymerase chain reaction analyses revealed that the expression of TßRIII was significantly elevated in human cardiac hypertrophic samples. Consistently, TßRIII expression was substantially increased in transverse aortic constriction (TAC)- and isoproterenol-induced mouse cardiac hypertrophy in vivo and in isoproterenol-induced cardiomyocyte hypertrophy in vitro. Overexpression of TßRIII resulted in cardiomyocyte hypertrophy, whereas isoproterenol-induced cardiomyocyte hypertrophy was greatly attenuated by knockdown of TßRIII in vitro. Cardiac-specific transgenic expression of TßRIII independently led to cardiac hypertrophy in mice, which was further aggravated by isoproterenol and TAC treatment. Cardiac contractile function of the mice was not altered in TßRIII transgenic mice; however, TAC led to significantly decreased cardiac contractile function in TßRIII transgenic mice compared with control mice. Conversely, isoproterenol- and TAC-induced cardiac hypertrophy and TAC-induced cardiac contractile function impairment were partially reversed by suppression of TßRIII in vivo. Our data suggest that TßRIII mediates stress-induced cardiac hypertrophy through activation of Ca(2+)/calmodulin-dependent protein kinase II, which requires a physical interaction of ß-arrestin2 with both TßRIII and calmodulin-dependent protein kinase II. Our findings indicate that stress-induced increase in TßRIII expression results in cardiac hypertrophy through ß-arrestin2-dependent activation of calmodulin-dependent protein kinase II and that transforming growth factor-ß and ß-adrenergic receptor signaling are not involved in spontaneous cardiac hypertrophy in cardiac-specific transgenic expression of TßRIII mice. Our findings may provide a novel target for control of myocardial hypertrophy.

Angiotensin-Converting Enzyme 3 (ACE3) Protects Against Pressure Overload-Induced Cardiac Hypertrophy.

BACKGROUND: Angiotensin-converting enzyme 3 (ACE3) is a recently defined homolog of ACE. However, the pathophysiological function of ACE3 is largely unknown. Here, we aim to explore the role of ACE3 in pathological cardiac hypertrophy. METHODS AND RESULTS: Neonatal rat cardiomyocytes (NRCMs) with gain and loss of function of ACE3 and mice with global knockout or cardiac-specific overexpression of ACE3 were used in this study. In cultured cardiomyocytes, ACE3 conferred protection against angiotensin II (Ang II)-induced hypertrophic growth. Cardiac hypertrophy in mice was induced by aortic banding (AB) and the extent of hypertrophy was analyzed through echocardiographic, pathological, and molecular analyses. Our data demonstrated that ACE3-deficient mice exhibited more pronounced cardiac hypertrophy and fibrosis and a strong decrease in cardiac contractile function, conversely, cardiac-specific ACE3-overexpressing mice displayed an attenuated hypertrophic phenotype, compared with control mice, respectively. Analyses of the underlying molecular mechanism revealed that ACE3-mediated protection against cardiac hypertrophy by suppressing the activation of mitogen-activated protein kinase kinase (MEK)-regulated extracellular signal-regulated protein kinase (ERK1/2) signaling, which was further evidenced by the observation that inhibition of the MEK-ERK1/2 signaling by U0126 rescued the exacerbated hypertrophic phenotype in ACE3-deficient mice. CONCLUSIONS: Our comprehensive analyses suggest that ACE3 inhibits pressure overload-induced cardiac hypertrophy by blocking the MEK-ERK1/2 signaling pathway.