Cyp2c44 gene disruption exacerbated pulmonary hypertension and heart failure in female but not male mice.
Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH. Since CYP2C44 is a functionally important epoxygenase, we hypothesized that knockout of the Cyp2c44 gene would protect both sexes of mice from hypoxia-induced PH. We tested this hypothesis in wild-type (WT) and Cyp2c44 knockout (Cyp2c44 (-/-)) mice exposed to normoxia (room air) and hypoxia (10% O2) for 5 weeks. Exposure of WT and Cyp2c44 (-/-) mice to hypoxia resulted in pulmonary vascular remodeling, increased pulmonary artery resistance, and decreased cardiac function in both sexes. However, in female Cyp2c44 (-/-) mice, compared with WT mice, (1) pulmonary artery resistance and right ventricular hypertrophy were greater, (2) cardiac index was lower, (3) left ventricular and arterial stiffness were higher, and (4) plasma aldosterone levels were higher, but (5) there was no difference in levels of EET in lungs and heart. Paradoxically and unexpectedly, we found that Cyp2c44 disruption exacerbated hypoxia-induced PH in female but not male mice. We attribute exacerbated PH in female Cyp2c44 (-/-) mice to elevated aldosterone and as-yet-unknown systemic factors. Therefore, we suggest a role for the human CYP2C genes in protecting women from severe PH and that this could be one of the underlying causes for a better 5-year survival rate in women than in men.
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Sachindra Raj
SR
Joshi
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Anand
A
Lakhkar
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Vidhi
V
Dhagia
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Ariadne L
AL
Zias
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Vasiliki
V
Soldatos
Department of Pharmacology, University of South Alabama, Mobile, Alabama, USA.
Kaori
K
Oshima
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Houli
H
Jiang
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Katherine
K
Gotlinger
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Jorge H
JH
Capdevila
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Michal L
ML
Schwartzman
Department of Pharmacology, University of South Alabama, Mobile, Alabama, USA.
Ivan F
IF
McMurtry
Department of Pharmacology, School of Medicine, New York Medical College, Valhalla, New York, USA.
Sachin A
SA
Gupte
aldosterone; arachidonic acid; cytochrome P450; sex; vascular remodeling
Am J Cardiol. 1998 Jul 15;82(2):254-5
9678304
FASEB J. 2008 Dec;22(12 ):4306-15
18725458
Circulation. 2012 Aug 28;126(9):1087-98
22859684
Br J Pharmacol. 2014 Feb;171(3):567-79
23802760
Am J Physiol Renal Physiol. 2014 Aug 15;307(4):F453-60
24966089
Physiol Rev. 2012 Jan;92(1):101-30
22298653
J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S20-31
19555855
J Pharmacol Exp Ther. 2004 Sep;310(3):845-54
15084647
J Renin Angiotensin Aldosterone Syst. 2015 Dec;16(4):1085-94
25031293
Am J Respir Crit Care Med. 2010 Dec 15;182(12):1554-62
20833821
Am J Respir Crit Care Med. 2000 Jun;161(6):1917-23
10852767
Am J Respir Crit Care Med. 2014 Aug 15;190(4):456-67
24956156
Pulm Circ. 2013 Apr;3(2):294-314
24015330
Front Physiol. 2015 Jun 30;6:188
26175691
Int J Clin Pract Suppl. 2010 Nov;(168):5-13
20939841
Curr Opin Nephrol Hypertens. 2013 Mar;22(2):163-9
23302865
J Hypertens. 2009 Feb;27(2):322-31
19226702
Am J Hypertens. 2008 Dec;21(12):1278-9
19020509
Am J Physiol Lung Cell Mol Physiol. 2014 Jul 1;307(1):L7-26
24816487
Hypertension. 2012 Feb;59(2):339-47
22184322
Hypertension. 2006 Apr;47(4):762-70
16505204
Prostaglandins Other Lipid Mediat. 2015 Jan-Mar;116-117:124-30
25526688
Hypertens Res. 2011 May;34(5):630-9
21307870
Eur Respir Rev. 2014 Dec;23(134):450-7
25445943
Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L335-43
10666118
Heart. 2016 Mar;102(5):390-6
26869635
Compr Physiol. 2014 Jul;4(3):1017-55
24944029
Womens Health (Lond). 2010 Mar;6(2):285-96
20187732
Mol Endocrinol. 2003 Jul;17(7):1268-82
12663745
Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H517-31
16617127
J Biol Chem. 2014 Feb 14;289(7):4377-86
24368771
Curr Protoc Mouse Biol. 2011 Mar 1;1:71-83
21743841
Am J Physiol Lung Cell Mol Physiol. 2013 May 15;304(10 ):L678-88
23457185
Curr Opin Pharmacol. 2009 Jun;9(3):287-96
19297247
Am J Respir Cell Mol Biol. 2016 Apr;54(4):451-60
26744837
Am J Respir Crit Care Med. 2013 Sep 15;188(6):639-46
23822809
Circ Cardiovasc Imaging. 2010 Mar;3(2):157-63
20044514
Cardiovasc Res. 2010 Jan 1;85(1):232-40
19679679
Am J Respir Cell Mol Biol. 2010 Dec;43(6):740-9
20118222
Toxicol Sci. 2011 Dec;124(2):261-77
21920951
Am J Physiol Regul Integr Comp Physiol. 2010 Apr;298(4):R862-9
20130225
Cardiovasc Res. 2013 Jul 1;99(1):24-34
23519266
Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:2-7
23333581
Am J Respir Crit Care Med. 2011 Nov 15;184(10 ):1171-82
21868504
Am J Respir Cell Mol Biol. 2015 May;52(5):563-70
25233285
J Clin Invest. 2014 Jun;124(6):2341-7
24892708
Am J Respir Crit Care Med. 1998 Sep;158(3):917-23
9731026
J Clin Hypertens (Greenwich). 2012 Apr;14(4):198-205
22458740
Thromb Res. 2016 Feb;138:114-20
26709040
FASEB J. 2008 Dec;22(12):4096-108
18716027
Hypertension. 2004 May;43(5):957-62
15007028
Nat Protoc. 2008;3(9):1422-34
18772869
Am J Physiol Lung Cell Mol Physiol. 2009 Dec;297(6):L1013-32
19748998
Circulation. 2010 Jun 29;121(25):2747-54
20547927
Circulation. 2011 Nov 1;124(18):e466-8
22042931