Evaluation of angiotensin receptor functions in hair follicle cells

  • Prof Sadashiva Karnik, Molecular Cardiology Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
  • Russell Desnoyer, Molecular Cardiology Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
  • Dr Rajaganapathy Jagannathan, Molecular Cardiology Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
  • Dr Pratima Karnik, Skin Diseases Research Center, Case Western Reserve University, Cleveland, OH, United States

Background: Vascular complications as well as high glucose increase Angiotensin II (Ang II) levels in skin cells by ten-fold. Ang II stimulates oncogene (myc) and growth factor (TGFb) gene expression after binding to Ang II-receptors receptors present in anagen hair follicles, switching the cells to a fibrogenic phenotype. Thus Ang II is a risk factor promoting follicular fibrosis and hair-loss and Ang II receptor blockers may be protective.
Purpose: Aim of this study was to correlate AngII-receptor dependent histone-code with phenotypic modulation in anagen hair follicle cells and specifically the histone code association with fibrogenic phenotype.
Methods: The outer root sheath cells stained positively with the AngII type 1 receptor (AT1R). Histones acid extracted from untreated, Ang II-treated and AT1R antagonist (candesartan) treated cells were analyzed for specific histone modifications by mass spectrometry. Three specific AT1R-modulated histone modifications were further characterized immunohistochemically in sub-pressor AngII infusion and diabetic mouse models. The expression of genes, myc, TGFb, collagen and fibronectin was monitored by real time PCR. Chromatin immunoprecipitation was used to evaluate association of specific histone modification with gene promoters.
Results: AT1R activation by Ang II increased H3-Lys23 acetylation and H2A-Lys125 methylation correlated with induced transcription of TGFb, collagen-A and fibronectin genes. These Ang II-induced changes were blocked by candesartan. Surprisingly, candesartan treatment induced phosphorylation of histone H2A-Ser1 coupled to demethylation of H2A-Lys125.
Conclusion: AT1R modulates healthy or fibrogenic phenotype in hair follicle cells by inducing specific gene expression through modification of histones. These modifications are reversed by AT1R antagonist, candesartan. The ATR blockers may protect against hair loss in vascular disease and diabetes.

Supported by NIH ( HL083243).