Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy. Myocardin related transcription factor A (MRTFA, MKL1) is a multifaceted transcription factor, regulating diverse biological processes. However, a detailed understanding of the mechanistic role of MKL1 in AAA has yet to be elucidated. In this study, we showed induced MKL1 expression in thoracic and abdominal aneurysmal tissues, respectively in both mice and humans. MKL1 global knockout mice displayed reduced AAA formation and aortic rupture compared with wild-type mice. Both gene deletion and pharmacological inhibition of MKL1 markedly protected mice from aortic dissection, an early event in Angiotensin II (Ang II)-induced AAA formation. Loss of MKL1 was accompanied by reduced senescence/proinflammation in the vessel wall and cultured vascular smooth muscle cells (VSMCs). Mechanistically, a deficiency in MKL1 abolished AAA-induced p38 mitogen activated protein kinase (p38MAPK) activity. Similar to MKL1, loss of MAPK14 (p38α), the dominant isoform of p38MAPK family in VSMCs suppressed Ang II-induced AAA formation, vascular inflammation, and senescence marker expression. These results reveal a molecular pathway of AAA formation involving MKL1/p38MAPK stimulation and a VSMC senescent/proinflammatory phenotype. These data support targeting MKL1/p38MAPK pathway as a potential effective treatment for AAA.
BackgroundThe nonHDLc/HDLc ratio (in which nonHDLc is defined as total cholesterol minus HDLc) is positively associated with multiple dyslipidemia-related disorders. This study aimed to determine whether the nonHDLc/HDLc ratio is an independent predictor of new-onset NAFLD (non-alcoholic fatty liver disease) in Chinese population.MethodsA perspective cohort study consisting of 3374 Chinese adults without liver diseases or metabolic disturbances was performed. Anthropometric parameters and data of metabolic and plasma lipid profile were collected. Univariate and multivariate Cox proportional analyses were carried out to evaluate the association of the nonHDLc/HDLc ratio with incident NAFLD. ROC curve analysis was preformed to compare the predictive value between the nonHDLc/HDLc and the nonHDLc for NAFLD.ResultsTwo thousand seven hundred seventeen participants were included in the final analysis. During a median follow-up period of 1.6 years, 264 participants (9.71%) developed NAFLD. After adjustment for potential confounders, a high nonHDLc/HDLc ratio (highest tertile) was associated with elevated risk of NAFLD (HR = 2.66; 95% CI, 1.13–6.24; P = 0.025 in female and HR = 2.11; 95% CI, 1.15–3.90; P = 0.016 in male). A nonlinear relationship was observed when the nonHDLc/HDLc ratio was ≤3.5. AUC values for nonHDLc/HDLc ratios (0.717 in female and 0.682 in male) were significantly higher than nonHDLc (0.675 in female and 0.653 in male) (P = 0.049 in female and P = 0.037 in male). In addition, the optimal cut-off value of nonHDLc/HDLc ratio for detection of NAFLD was 2.4 in female and 2.3 in male.ConclusionsThe nonHDLc/HDLc ratio is an independent predictor of NAFLD and a stronger predictor than nonHDLc in Chinese population, which might be expected to better guide early identification of individuals at risk of NAFLD.
Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.
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