title: Parathyroid hormone-related peptide protects cardiomyocytes from oxidative stress-induced cell death: First evidence of a novel endocrine-cardiovascular interaction.
abstract: Although there is a growing interest in the molecular cross-talk between the endocrine and cardiovascular systems, the cardiac effects of calcium-regulating hormones (i.e., parathyroid hormone-related peptide (PTHrP)) have not been explored. In this study, we examined the effect of PTHrP on the viability of isolated adult mouse cardiomyocytes subjected to oxidative stress. Myocytes from 19 to 22 week old male 129J/C57BL6 mice were exposed to oxidative insult in the form of H2O2 which led to more than 70% loss of cell viability. Herein we demonstrate, for the first time, that pretreatment with 100 nM PTHrP prior to 100 μM H2O2 incubation prevents H2O2 -induced cell death by more than 50%. Immunoblot analysis revealed H2O2 induction of MKP-1 protein expression while PTHrP decreased MKP-1 expression. Moreover, myocytes derived from MKP1 KO mice were resistant to oxidative injury. No added benefit of PTHrP treatment was noted in MKP-1 null cardiomyocytes. Using specific pharmacological inhibitors we demonstrated that P-p38, P-ERK and P-AKT mediated PTHrP's cardioprotective action. These data provide novel evidence that: i) down-regulation of MKP1 affords profound protection against oxidative stress; and ii) PTHrP is cardioprotective, possibly via down-regulation of MKP-1 and activation of MAPK and PI3K/AKT signaling.
authors.affiliation: Department of Internal Medicine/Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: ndatta@med.wayne.edu.
authors.forename: Nabanita S
authors.initials: NS
authors.lastname: Datta
authors.affiliation: Department of Internal Medicine/Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Sahiti
authors.initials: S
authors.lastname: Chukkapalli
authors.affiliation: Department of Internal Medicine/Endocrinology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Vengalil
authors.affiliation: Department of Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Enbo
authors.initials: E
authors.lastname: Zhan
authors.affiliation: Department of Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Przyklenk
authors.affiliation: Department of Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lasley
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D044162:Parathyroid Hormone-Related Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: Cardioprotection; MAPK phosphatase-1; PI3K/AKT; PTHrP