title: Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptor.
abstract: Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12-14/group): control (vehicle); nitro-L-arginine methyl ester (L-NAME) an NO synthase inhibitor; simvastatin (SIM), an NO synthase activator; and SIM+L-NAME. Serial echocardiography was performed and blood pressure (BP) at 6 weeks was recorded using a micromanometer. Myocardial eNOS and mitogen-activated protein kinase (MAPK, including ERK, p38, and JNK) protein expression were measured. Results showed that (i) B2RKO mice had significantly lower ejection fraction than did WT mice (61% +/- 1% vs. 73% +/- 1%), lower myocardial eNOS and phospho-eNOS, normal systolic BP, and higher LV mass, phospho-p38, and JNK; (ii) L-NAME increased systolic BP in KO mice (117 +/- 19 mm Hg) but not in WT mice and exacerbated LV hypertrophy and dysfunction; and (iii) in KO mice, SIM decreased hypertrophy, p38, and JNK, improved function, increased capillary eNOS and phospho-eNOS, and prevented L-NAME-induced LV hypertrophy without lowering BP. We conclude that disruption of the B2R causes maladaptive cardiac hypertrophy with myocardial eNOS downregulation and MAPK upregulation. SIM reverses these abnormalities and prevents the development of primary cardiac hypertrophy as well as hypertrophy secondary to L-NAME-induced hypertension.
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.forename: Faisal H
authors.initials: FH
authors.lastname: Cheema
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Martens
authors.forename: Naila
authors.initials: N
authors.lastname: Mahmut
authors.forename: Caroline
authors.initials: C
authors.lastname: Kinnear
authors.forename: Ana M D
authors.initials: AM
authors.lastname: Gonzalez
authors.forename: William
authors.initials: W
authors.lastname: Bonney
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
authors.forename: Seema
authors.initials: S
authors.lastname: Mital