Abstract

Chromogranin A (CHGA) is a 48 kDa acidic proprotein giving rise to biologically active peptides including a novel fragment (bovine CHGA344-364; human CHGA352-372) which we have discovered and called """"""""catestatin,"""""""" that acts as a potent (IC50 about200-400 nM) and specific inhibitor of nicotine-induced catecholamine (CA) secretion and agonist desensitization. We have recently generated CHGA knockout (Chga-/-) mice that displayed higher systolic (SBP) and diastolic blood pressure (DBF), and non-dipping. We also identified 3 naturally occurring human catestatin variants (Gly364Ser, Pro370Leu, Arg374Gln). We found that Gly364Ser variant causes profound alteration in human autonomic activity. This proposal explores the mechanism of development of hypertension in Chga-/- mice, modulation by nicotine, mechanism of action of catestatin variants in su perfused rat adrenal gland and generation of catestatin variants through 4 specific aims:
Aim I. Explore the mechanism of development of higher SBP and DBP in Chga-/- mice and nicotinic modulation of BP phenotype. """"""""Rescue"""""""" the elevated BP phenotype in Chga-/- mice by introduction of a bacterial artificial chromosome (BAG) containing the human CHGA gene (CHGA +) into the germline of Chga-/- mice.
Aim II. Generation of mice with conditional Chga-/- in phenylethanolamine N-methyl transferase (Chga-Pnmt-/-) producing cells, to determine whether ablation of Chga restricted to adrenergic cells is sufficient to cause hypertension and its associated nicotinic response alterations.
Aim III. Determine the effects of human catestatin variants (Gly364Ser, Pro370Leu, Arg374Gln) on nicotine-evoked CA secretion from superfused rat adrenal gland and desensitization.
Aim I V. Proteolytic processing of human CHGA to generation of human catestatin variants. These studies, utilizing unique knockout, transgenic, and human variants of catestatin, are likely to establish novel catestatin mechanisms in the development of hypertension and its modulation through nicotinic-cholinergic receptors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011311-09
Application #
7387429
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Purohit, Vishnudutt
Project Start
1997-09-30
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$179,455
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Friese, Ryan S; Altshuler, Angelina E; Zhang, Kuixing et al. (2013) MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. Hum Mol Genet 22:3624-40
Bandyopadhyay, Gautam K; Vu, Christine U; Gentile, Stefano et al. (2012) Catestatin (chromogranin A(352-372)) and novel effects on mobilization of fat from adipose tissue through regulation of adrenergic and leptin signaling. J Biol Chem 287:23141-51
Mahata, Manjula; Zhang, Kuizing; Gayen, Jiaur R et al. (2011) Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin. Cell Tissue Res 345:87-102
Sinha-Hikim, Indrani; Shen, Ruoqing; Nzenwa, Ify et al. (2011) Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure. Apoptosis 16:563-73
Gayen, Jiaur R; Zhang, Kuixing; RamachandraRao, Satish P et al. (2010) Role of reactive oxygen species in hyperadrenergic hypertension: biochemical, physiological, and pharmacological evidence from targeted ablation of the chromogranin a (Chga) gene. Circ Cardiovasc Genet 3:414-25
Dev, Nagendu B; Gayen, Jiaur R; O'Connor, Daniel T et al. (2010) Chromogranin a and the autonomic system: decomposition of heart rate variability and rescue by its catestatin fragment. Endocrinology 151:2760-8
Schafer, M K-H; Mahata, S K; Stroth, N et al. (2010) Cellular distribution of chromogranin A in excitatory, inhibitory, aminergic and peptidergic neurons of the rodent central nervous system. Regul Pept 165:36-44
Biswas, Nilima; Curello, Erica; O'Connor, Daniel T et al. (2010) Chromogranin/secretogranin proteins in murine heart: myocardial production of chromogranin A fragment catestatin (Chga(364-384)). Cell Tissue Res 342:353-61
Vaingankar, Sucheta M; Li, Ying; Biswas, Nilima et al. (2010) Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responses. J Hypertens 28:817-25
Gu, Yusu; Zhang, Kuixing; Biswas, Nilima et al. (2010) Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity. Endocrinology 151:4820-9

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