title: Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner.
abstract: Sex differences exist in the hypertrophic response, cardiac remodeling, and transition to heart failure of hypertensive patients, and while some of these differences are likely influenced by estrogen, the genetic pathways downstream of estrogen that impact on cardioprotection have yet to be fully elucidated. We have previously shown that the cardioprotective effects of adrenomedullin (AM), an emerging clinical biomarker for cardiovascular disease severity, vary with sex in mouse models. AM signaling during cardiovascular stress is strongly modulated by receptor activity-modifying protein 3 (RAMP3) via its interaction with the G protein-coupled receptor calcitonin receptor-like receptor (CLR). Like AM, RAMP3 expression is potently regulated by estrogen, and so we sought to determine the consequences of genetic Ramp3 loss on cardiac adaptation to chronic hypertension, with a particular focus on characterizing potential sex differences. We generated and bred RAMP3(-/-) mice to RenTgMK mice that consistently display severe angiotensin II-mediated CV disease and compared CV disease progression in RenTgMK to that of RenTgMK:RAMP3(-/-) offspring. As expected, RAMP3 gene expression was higher in cardiovascular tissues of RenTgMK mice and more strongly up-regulated in female RenTgMK mice relative to wildtype controls. RAMP3 loss did not affect the development of hypertension or the presence and severity of perivascular and interstitial fibrosis in the left ventricle (LV). However, echocardiography revealed that while RenTgMK mice developed concentric cardiac hypertrophy with sustained systolic function, male RenTgMK:RAMP3(-/-) mice showed evidence of LV chamber dilatation and depressed systolic function, suggestive of cardiac decompensation. Consistent with these measures of heart failure, male RenTgMK:RAMP3(-/-) mice had increased cardiac apoptosis and elevated activation of Akt. These phenotypes were not present in female RenTgMK:RAMP3(-/-) mice. Collectively, these data demonstrate a sex-dependant, cardioprotective role of RAMP3 in the setting of chronic hypertension.
authors.affiliation: Department of Cell & Molecular Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Cordelia J
authors.initials: CJ
authors.lastname: Barrick
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lenhart
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Dackor
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nagle
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Caron
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D056726:Genetic Association Studies; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics; D012737:Sex Factors
chemical_list: D058264:Receptor Activity-Modifying Protein 3; D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin
references.citation: Biochem Pharmacol. 2003 Dec 1;66(11):2107-15
references.pmid: 14609735
references.citation: Hypertension. 2003 Mar;41(3):512-8
references.pmid: 12623952
references.citation: Mol Cell Biol. 2006 Apr;26(7):2511-8
references.pmid: 16537897
references.citation: Eur J Heart Fail. 2009 Apr;11(4):361-6
references.pmid: 19190023
references.citation: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1524-30
references.pmid: 16627800
references.citation: Pharmacol Ther. 2006 Jan;109(1-2):173-97
references.pmid: 16111761
references.citation: Endocrinology. 2002 Sep;143(9):3515-21
references.pmid: 12193565
references.citation: Biochemistry. 2009 Dec 15;48(49):11773-85
references.pmid: 19886671
references.citation: Peptides. 2010 Apr;31(4):579-84
references.pmid: 20034525
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Mar;280(3):L547-54
references.pmid: 11159039
references.citation: J Clin Invest. 2008 Jan;118(1):40-50
references.pmid: 18097475
references.citation: Pharmacol Ther. 2006 Sep;111(3):909-27
references.pmid: 16616959
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3106-11
references.pmid: 14978280
references.citation: Circulation. 2000 Feb 8;101(5):498-503
references.pmid: 10662746
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8248-52
references.pmid: 12034874
references.citation: Nature. 1998 May 28;393(6683):333-9
references.pmid: 9620797
references.citation: Curr Med Chem Cardiovasc Hematol Agents. 2005 Jul;3(3):231-42
references.pmid: 15974887
references.citation: Circulation. 2004 Jan 20;109(2):242-8
references.pmid: 14691041
references.citation: Microcirculation. 2004 Jan-Feb;11(1):9-38
references.pmid: 15280095
references.citation: Regul Pept. 2003 Apr 15;112(1-3):71-8
references.pmid: 12667627
references.citation: Pediatr Cardiol. 2011 Mar;32(3):354-9
references.pmid: 21279340
references.citation: Hypertension. 2004 Jan;43(1):109-16
references.pmid: 14662648
references.citation: JAMA. 2002 Jul 17;288(3):321-33
references.pmid: 12117397
references.citation: Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1506-14
references.pmid: 12805025
references.citation: Basic Res Cardiol. 2006 May;101(3):193-203
references.pmid: 16450076
references.citation: Biochem Biophys Res Commun. 2002 Jun 7;294(2):340-6
references.pmid: 12051717
references.citation: Contemp Top Lab Anim Sci. 2005 Sep;44(5):43-6
references.pmid: 16138782
references.citation: J Cell Sci. 2005 Oct 15;118(Pt 20):4709-20
references.pmid: 16188935
references.citation: Circulation. 2007 Jun 26;115(25):3197-204
references.pmid: 17562954
references.citation: Physiol Genomics. 2005 Jan 20;20(2):203-9
references.pmid: 15585607
references.citation: Herz. 2005 Aug;30(5):356-67
references.pmid: 16132238
references.citation: Peptides. 2007 Nov;28(11):2164-70
references.pmid: 17889965
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2659-68
references.pmid: 18424632
references.citation: J Biol Chem. 2005 Jun 24;280(25):23926-35
references.pmid: 15805108
references.citation: J Biol Chem. 2007 Jun 22;282(25):18094-18099
references.pmid: 17470425
references.citation: Am J Hypertens. 2009 Aug;22(8):860-6
references.pmid: 19424162
references.citation: Mol Endocrinol. 2005 Mar;19(3):657-68
references.pmid: 15528273
references.citation: J Biol Chem. 2005 Mar 11;280(10):9297-307
references.pmid: 15613468
references.citation: Biochem Biophys Res Commun. 2000 Apr 29;271(1):197-202
references.pmid: 10777702
references.citation: Circ Res. 2004 Oct 1;95(7):692-9
references.pmid: 15345655
references.citation: Eur J Heart Fail. 2010 May;12(5):484-91
references.pmid: 20215339
references.citation: J Biol Chem. 2003 Jan 31;278(5):3293-7
references.pmid: 12446722
references.citation: J Clin Invest. 2005 Aug;115(8):2128-38
references.pmid: 16007268
references.citation: Am J Physiol Cell Physiol. 2002 Jun;282(6):C1322-31
references.pmid: 11997247
references.citation: Regul Pept. 2005 Apr 15;127(1-3):239-44
references.pmid: 15680493
references.citation: J Mol Cell Cardiol. 2005 Jan;38(1):145-51
references.pmid: 15623431
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H469-76
references.pmid: 15374829
references.citation: Biochem Biophys Res Commun. 2000 Apr 2;270(1):89-93
references.pmid: 10733909
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3420-5
references.pmid: 17360661
references.citation: J Mol Endocrinol. 2006 Feb;36(1):81-9
references.pmid: 16461929
references.citation: Mol Endocrinol. 2007 Apr;21(4):783-96
references.pmid: 17053041
references.citation: Curr Opin Nephrol Hypertens. 2011 Mar;20(2):133-8
references.pmid: 21178615
references.citation: Prog Mol Biol Transl Sci. 2010;91:53-79
references.pmid: 20691959
references.citation: Mol Pharmacol. 1999 Jul;56(1):235-42
references.pmid: 10385705
references.citation: J Pharmacol Exp Ther. 2006 Mar;316(3):1269-81
references.pmid: 16326922
references.citation: J Cardiovasc Transl Res. 2009 Sep;2(3):228-39
references.pmid: 19668346
references.citation: Cardiovasc Hematol Disord Drug Targets. 2006 Jun;6(2):125-32
references.pmid: 16787197
references.citation: Trends Pharmacol Sci. 2003 Nov;24(11):596-601
references.pmid: 14607083
references.citation: J Am Coll Cardiol. 2007 Apr 10;49(14):1525-32
references.pmid: 17418290
references.citation: Am Heart J. 2006 Jul;152(1):170-6
references.pmid: 16824852
references.citation: Hypertens Res. 2003 Feb;26 Suppl:S99-104
references.pmid: 12630818
references.citation: Mol Cell Biochem. 2005 Jan;268(1-2):103-10
references.pmid: 15724443
references.citation: Mol Cell Endocrinol. 2000 Apr 25;162(1-2):35-43
references.pmid: 10854696