Chromogranin a and the autonomic system: decomposition of heart rate variability and rescue by its catestatin fragment.
Chromogranin A (CHGA/Chga) has been implicated in the genesis of systemic hypertension and consequent cardiac abnormalities. Catestatin (CST) (human CHGA(352-372)) replacement reduces blood pressure elevation and increases baroreflex sensitivity in Chga knockout (KO) mice. Because of the dampened baroreflex sensitivity, we reasoned that KO mice would display altered heart rate variability (HRV). Thus, we evaluated beat-to-beat measurements in HRV in wild-type (WT) and KO mice, before and after CST replacement. HR dynamics were evaluated by bipolar Einthoven electrocardiogram, with deconvolution into time and frequency domains, as well as Lorenz nonlinear return analyses. At baseline, HR was higher [444 +/- 24 beats per minute (bpm)] in KO compared with WT (330 +/- 18 bpm) mice. The total power in the HRV spectra was substantially diminished in KO animals. CST increased total power but only in KO mice. Each time-domain parameter was substantially lower in KO compared with WT mice, and the CST in the KO group could reverse the differences. Lorenz analysis revealed reductions in S1 (short axis perpendicular to the line of identity in the ellipse) and S2 (long axis along the line of identity in the ellipse) in KO animals, indicating that regulation of HRV is diminished in the parasympathetic and sympathetic domains. CST replacement caused restoration of both S1 and S2, in the KO group. These data suggest that Chga has a profound effect on autonomic tone to the heart and that its CST fragment is responsible for such actions. The results suggest future strategies for intervention in cardiovascular disorders accompanied by adverse HRV profiles.
Dev
Nagendu B
NB
Department of Medicine (0838), University of California, San Diego, and Veterans Affairs San Diego Healthcare System, 9500 Gilman Drive, La Jolla, California 92093-0838, USA.
Gayen
Jiaur R
JR
O'Connor
Daniel T
DT
Mahata
Sushil K
SK
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000378:metabolism; D053379:Chromogranin A / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology*
D053379:Chromogranin A; D010446:Peptide Fragments; C109084:chromogranin A (344-364)
Acta Physiol (Oxf). 2008 Feb;192(2):309-24
18005393
Endocrinology. 2009 Nov;150(11):5027-35
19819970
Curr Protein Pept Sci. 2003 Apr;4(2):97-104
12678849
Masui. 2006 Apr;55(4):436-40
16634545
J Clin Invest. 1997 Sep 15;100(6):1623-33
9294131
Circ Res. 1998 Mar 9;82(4):416-23
9506701
J Biol Chem. 2009 Oct 16;284(42):28498-509
19706599
Physiol Meas. 2002 Nov;23(4):671-82
12450268
Mol Pharmacol. 2004 Nov;66(5):1180-91
15326220
Arch Mal Coeur Vaiss. 2003 Oct;96(10):955-62
14653055
Ann Intern Med. 1980 Feb;92(2 Pt 2):304-7
7356218
J Hypertens Suppl. 1984 Dec;2(3):S147-50
6599663
Cardiovasc Res. 2008 Aug 1;79(3):527-36
18349137
Am J Hum Genet. 2004 Feb;74(2):197-207
14740315
Biomed Eng Online. 2009 Jan 29;8:3
19178728
Q J Med. 1980 Winter;49(193):95-108
7433630
Nat Biotechnol. 2009 Jun;27(6):567-71
19448630
J Clin Invest. 2005 Jul;115(7):1942-52
16007257
Eur Heart J. 2002 Jun;23(12):967-74
12069452
Kidney Int. 2008 Jul;74(1):115-25
18432188
Endocrinology. 2008 Oct;149(10):4780-93
18535098
Mol Endocrinol. 2000 Oct;14(10):1525-35
11043569
Am J Cardiol. 1997 Jun 15;79(12):1645-50
9202356
Diabetes. 1982 Apr;31(4 Pt 1):339-45
7152130
Hypertension. 1998 Aug;32(2):293-7
9719057
Stroke. 2003 Oct;34(10):2446-50
12958326
J Auton Pharmacol. 1994 Jun;14(3):187-200
7929473
J Am Coll Cardiol. 2001 Jun 15;37(8):2136-43
11419900
Kidney Int. 1990 Mar;37(3):955-64
2313983
Am J Cardiol. 1987 Feb 1;59(4):256-62
3812275
Circulation. 1996 Mar 1;93(5):1043-65
8598068
Regul Pept. 1992 Sep 3;41(1):9-18
1455014
Circulation. 2007 May 1;115(17):2271-81
17438154
Am J Cardiol. 2000 Aug 1;86(3):309-12
10922439
J Hypertens. 2002 Jul;20(7):1335-45
12131530
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H113-22
18469147
Int J Cardiol. 2009 Aug 14;136(2):211-3
18606470
Hypertension. 1990 Mar;15(3):237-46
2406199
Immunopharmacology. 1999 Dec;45(1-3):21-7
10614985
N Engl J Med. 2003 Mar 20;348(12):1134-49
12646671
Ann Noninvasive Electrocardiol. 2006 Apr;11(2):154-62
16630090
Peptides. 2008 Nov;29(11):1943-52
18638516
Peptides. 1998;19(7):1241-8
9786174
Curr Atheroscler Rep. 2002 Mar;4(2):120-7
11822975
Neuroscience. 1992 Aug;49(3):497-528
1501763
Int J Cardiol. 1996 Mar;53(3):291-8
8793584
Circulation. 1995 Apr 1;91(7):1936-43
7895350
Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H733-40
10924073
Am J Cardiol. 1989 Nov 15;64(18):1162-7
2816768