Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptor 1

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; simvastain (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. i ) B2R disruption predisposed to early onset on maladaptive cardiac hypertrophy, which is likely related to reduced myocardial eNOS and (or) increased p38 and JNK activation; ( ii ) B2R disruption also predisposed to the development of systemic hypertension in conditions of reduced NO bioavailability; and finally, ( iii ) SIM prevented the development of cardiac hypertrophy and dysfunction caused by B2R disruption by reversing the downstream effects of disruption of the B2R on myocardial eNOS and MAPK activation. These results indicate that targeted pharmacologic intervention can be used to reverse the phenotypic effects of a single gene defect. Our study provides a possible mechanism, that is, reduced NO and altered MAPK signaling, to explain this effect. The B2R genotype can also influence response to therapy. Hallberg reported that patients with the B2R +9/+9 genotype (impaired receptor function) demonstrate incomplete reversal of LV hypertrophy in response to standard antihypertensive therapy using angiotensin receptor blockers or beta blockers. Duka reported that ACE inhibition worsens cardiac function in mice lacking the B2R, possibly related to overexpression of B1R that can have noxious proinflammatory effects. In our study, B1R expression was not different in WT compared with KO mice and was unaffected by SIM treatment. The lack of effect on the B1R suggests that SIM may be better tolerated in B2RKO mice. Our findings suggest an alternate choice of pharmacotherapy that may be both safer and more beneficial in clinical practice since it specifically targets molecular pathways disrupted downstream of the single gene defect. A drug like SIM that normalizes both NO signaling as well as the abnormalities in MAPK signaling may be more effective in subjects with B2R genotype abnormalities by specifically targeting the downstream pathways disrupted by B2R inactivation. SIM also provides end-organ protection independent of hemodynamic effects. This has implications for the tailored use of medical therapy to rescue the cardiac phenotype caused by a single gene defect.