title: Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease.
abstract: BACKGROUND
  Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior.
  
  
  METHODS
  We compared heart (n=54) and serum (n=162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed.
  
  
  RESULTS
  Cardiac fibrosis increased 12% and 77% in stage 3-4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3-4 CKD and ESRD (P trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P=0.02), decreased proliferation (P=0.03), and induced EndMT.
  
  
  CONCLUSIONS
  CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.
authors.affiliation: Renal Division, Department of Medicine, Brigham & Women's Hospital, Boston, MA, United States. Electronic address: dcharytan@partners.org.
authors.forename: David M
authors.initials: DM
authors.lastname: Charytan
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, MA, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.affiliation: Renal Division, Department of Medicine, Brigham & Women's Hospital, Boston, MA, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Helfand
authors.affiliation: Department of Nephrology and Rheumatology, Georg-August University, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center, Georg-August University, Göttingen, Germany.
authors.forename: Xingbo
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center, Georg-August University, Göttingen, Germany.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Washington School of Medicine, MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.affiliation: Renal Division, Department of Medicine, Brigham & Women's Hospital, Boston, MA, United States.
authors.forename: Angeles
authors.initials: A
authors.lastname: Cinelli
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center, Georg-August University, Göttingen, Germany; DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zeisberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000097:blood*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000175:diagnosis
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D009569:Nitric Oxide
keywords: Angiogenesis inhibitor; CKD; Cardiovascular disease; ESRD; Endothelial to mesenchymal transition; Fibrosis