👤 Michael Lehrke

Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro . In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target. Show less

Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations. 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded. In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families. MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment. Show less

ApoA-IV, an apolipoprotein (apo) with antioxidant, antiatherogenic, and antiinflammatory properties, was recently demonstrated to inhibit dextran sulfate sodium (DSS)-induced experimental colitis in mice. We therefore hypothesized that apoA-IV may be associated with disease activity in patients with inflammatory bowel disease (IBD). We addressed this question by testing for associations between apoA-IV genotypes, apoA-IV plasma levels, inflammatory parameters, and clinical disease activity in 206 patients with Crohn's disease (CD), 95 subjects with ulcerative colitis (UC), and 157 healthy controls. In CD patients, apoA-IV plasma levels were inversely associated with C-reactive protein (CRP) (P = 0.005) and disease activity (P = 0.01) in univariate analysis. In multiple logistic regression analysis, apoA-IV levels were identified as an independent predictor of elevated CRP (odds ratio [OR] 0.956, 95% confidence interval [CI]: 0.916-0.998, P = 0.04) and active disease (OR 0.957, 95% CI: 0.918-0.998, P = 0.04). In UC patients the apoA-IV gene variant 360 His (P = 0.03) but not apoA-IV levels (P = 0.15) were associated with increased disease activity in univariate analysis. This association, however, was lost in multiple logistic regression analysis (OR 3.435, 95% CI 0.995-11.853, P = 0.05). To our knowledge, this is the first study to demonstrate an association of apoA-IV with disease activity in patients with CD. Further studies are needed to define the relationship of apoA-IV to IBD. Show less