title: A cell permeable peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model.
abstract: Cell permeable peptides (CPP) aid cellular uptake of targeted cargo across the hydrophobic plasma membrane. CPP-mediated cargo delivery of receptor signaling motifs provides an opportunity to regulate specific receptor initiated signaling cascades. Both endothelin-1 receptors, ETA and ETB, have been targets of antagonist therapies for individuals with pulmonary arterial hypertension (PAH). These therapies have had success but have been accompanied by adverse reactions. Also, unlike the CPP which target specific signaling cascades, the antagonists target the entire function of the receptor. Using the CPP strategy of biased antagonism of the ETB receptor's intracellular loop 2 (ICB2), we demonstrate blunting of hypoxic pulmonary hypertension (HPH) in the rat, including indices of pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular remodeling. Further, ex vivo analysis of the pulmonary artery treated with the IC2B peptide upon injection manifests marked reductions in Akt and ERK activation. Both kinases have been intimately related to cell proliferation and vascular contraction, the hallmarks of PAH. These observations in sum illustrate an involvement of the ETB receptor in HPH and furthermore provide a basis for a novel, CPP-based, strategy in the treatment of PAH, ultimately able to target not only ET-1, but also other factors involved in the development of PAH.
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Daniel S
authors: DS
authors: Green
authors: Chamila
authors: C
authors: Rupasinghe
authors: Rod
authors: R
authors: Warburton
authors: Jamie L
authors: JL
authors: Wilson
authors: Christine O
authors: CO
authors: Sallum
authors: Linda
authors: L
authors: Taylor
authors: Achani
authors: A
authors: Yatawara
authors: Dale
authors: D
authors: Mierke
authors: Peter
authors: P
authors: Polgar
authors: Nicholas
authors: N
authors: Hill
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019332:Endothelin-1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D058990:Molecular Targeted Therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D057846:Cell-Penetrating Peptides; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases