Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-β1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-β1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitationmass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-β1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI. Myocardial infarction (MI) has been the main cause of cardiovascular diseases for centuries and remains a major issue. Although improved survival from acute MI has been observed due to the effectiveness of revascularisation and other therapies, the incidence of heart failure has increased as a consequence of adverse ventricular remodelling 1,2. Among the factors involved in ventricular remodelling, cardiac fibrosis, which results from the disequilibrium of synthesis and deregulation of extracellular matrix, is a pivotal 3,4. In the acute stage, cardiac fibrosis, is a repairing process that protects the infarct heart from rupture; at the subacute and chronic stage, in cases where cardiac fibrosis abnormally persists, it inevitably leads to cardiac dysfunction and ventricular wall stiffness increasing the risk of heart failure 4,5. Thus, it is essential to control levels of cardiac fibrosis. Cardiac fibroblasts (CFs) are central mediators of the cardiac fibrotic response 6. CFs are mainly stimulated by TGFβ-1 following MI and differentiate into activated myofibroblasts which express α-smooth muscle actin (α-SMA). This results in the secretion of a large amount of extracellular matrix, including fibronectin and collagen I (Col1), which is, in part, regulated by the activation of Smad2/3 4,7,8. To date, no studies have fully elucidated how this process is regulated. The ubiquitin proteasome system (UPS), which consists of E1 ubiquitin-activating enzymes, E2 conjugating enzymes and E3 ubiquitin ligases and deubiquitinating enzymes, is responsible for the degradation and stability of the majority of proteins 9,10. Rece...
Coronavirus disease 2019 (COVID-19) is a recently emerged disease with formidable infectivity and high mortality. Emerging data suggest that diabetes is one of the most prevalent comorbidities in patients with COVID-19. Although their causal relationship has not yet been investigated, preexisting diabetes can be considered as a risk factor for the adverse outcomes of COVID-19. Proinflammatory state, attenuation of the innate immune response, possibly increased level of ACE2, along with vascular dysfunction, and prothrombotic state in people with diabetes probably contribute to higher susceptibility for SARS-CoV-2 infection and worsened prognosis. On the other hand, activated inflammation, islet damage induced by virus infection, and treatment with glucocorticoids could, in turn, result in impaired glucose regulation in people with diabetes, thus working as an amplification loop to aggravate the disease. Therefore, glycemic management in people with COVID-19, especially in those with severe illness, is of considerable importance. The insights may help to reduce the fatality in the effort against COVID-19.
An increasing body of evidence connects non-alcoholic fatty liver disease (NAFLD) to hypertension. The objective of this systematic review and meta-analysis was to estimate the nature and magnitude of the association between NAFLD and hypertension. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for observational studies published up to May 1, 2021. Cohort studies that reported data on the association between NAFLD and incident hypertension or between hypertension and incident NAFLD were included. We used random-effects models to conduct meta-analysis on the measures of association from individual studies. A total of 11 studies were eligible for inclusion, among which 4 studies including 25,260 participants reported the association between hypertension and new-onset NAFLD. The presence of hypertension was significantly associated with an increased risk of incident NAFLD (HR 1.63, 95% CI: 1.41–1.88; I2 = 37.6%). On the other hand, 9 studies with data on 46,487 participants analyzed the effects of NAFLD on incident hypertension. Pooled analysis showed that the presence of NAFLD was significantly associated with an increased incidence of hypertension (HR 1.55, 95% CI: 1.29–1.87; I2 = 80.5%). There was significant heterogeneity among the studies in this analysis ( p < 0.01). Sensitivity analyses showed that the magnitude of the association was significantly different in subgroups stratified by a mean age of participants and geographical location, which explains part of the heterogeneity. In conclusion, this meta-analysis indicates the existence of a bidirectional relationship between NAFLD and hypertension independent of traditional cardiometabolic risk factors.
Sirs:The meta-analysis of Li and colleagues entitled Prevalence and impact of cardiovascular metabolic diseases on in China indicated that patients with hypertension are more likely to develop severe/ICU cases after 2019-nCoV infection. Hypertension accounted for 28.8% of ICU/severe cases, but 14.1% of non-ICU/severe cases. Moreover, the proportion of hypertension was about twofold higher in ICU/severe cases than in their non-ICU/severe counterparts (risk raio (RR) 2.03 (1.54-2.68), p < 0.00001) [1]. However, these pooled results were obtained by analyzing data from only three studies, and moderate heterogeneity was shown (I 2 = 41%). More importantly, none of the three included studies adjusted baseline confounding factors between ICU/ severe cases and non-ICU/severe cases, so a large number of confounders such as age and gender may seriously affect the effect size of this association. In more recent studies, Chen and colleagues [2] reported that critically ill patients were more likely to have coexisting hypertension compared to mild cases (35 (27.8%) versus 14 (58.3%), p = 0.003). Univariate logistic regression analysis indicated that hypertension was significantly associated with the severity of ), p = 0.005). However, statistical significance was not reached in multivariate logistic regression model , p = 0.198), i.e. comorbid hypertension was not an independent risk factor for the severity of COVID-19 in this study. A recent retrospective cohort study reported that coexisting hypertension was more commonly seen in patients with ARDS than in those without it (16 (13.7%) versus 23 (27.4%), p = 0.02)
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