Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptor

• Published in: Canadian journal of physiology and pharmacology 2008-09, Vol.86 (9), p.633-642
• Main Authors: OSORIO, Juan C, CHEEMA, Faisal H, MARTENS, Timothy P, MAHMUT, Naila, KINNEAR, Caroline, GONZALEZ, Ana M. D, BONNEY, William, HOMMA, Shunichi, LIAO, James K, MITAL, Seema
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Pressure - physiology; Bradykinin; Cardiomegaly - diagnostic imaging; Cardiomegaly - drug therapy; Cardiomegaly - genetics; Cell receptors; Dosage and administration; Drug therapy; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Health aspects; Heart enlargement; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hypertrophy, Left Ventricular - diagnostic imaging; Hypertrophy, Left Ventricular - genetics; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - physiology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - ultrastructure; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - physiology; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1 - biosynthesis; Receptor, Bradykinin B1 - genetics; Receptor, Bradykinin B1 - physiology; Receptor, Bradykinin B2 - genetics; Receptor, Bradykinin B2 - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Simvastatin; Simvastatin - pharmacology; Stroke Volume - physiology; Ultrasonography; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/Y08-068

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.