Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure

Abstract

Background-The regulation of the cardiac neutral endopeptidase (EC 24.10, NEP) that degrades bradykinin and natriuretic peptides has been investigated in human cardiac hypertrophy and heart failure. Methods and Results-NEP mRNA was quantitated by real-time polymerase chain reaction (PCR) in left ventricular biopsies from patients with aortic valve stenosis (AS, nϭ19) and heart failure due to dilated cardiomyopathy (DCM, nϭ14), and control subjects with normal systolic function (CON, nϭ14). Left ventricular NEP mRNA content was increased 3-fold in AS (PϽ0.005) and 4.1-fold in DCM (PϽ0.002). The increase in NEP mRNA was related to the increase in end diastolic pressure in AS and DCM. In a second series, myocardial NEP enzymatic activity was determined. It increased 3.6-fold in AS (PϽ0.02) and 4-fold in DCM (PϽ0.002). NEP was localized in the myocardium by immunofluorescence microscopy and in situ PCR to myocytes and nonmyocyte areas and cells. Key Words: hypertrophy Ⅲ cardiomyopathy Ⅲ heart failure Ⅲ metalloproteinases N eutral endopeptidase (EC 24.10, NEP) catalyzes the degradation of vasodilator and growth-inhibitory peptides such as bradykinin and atrial and brain natriuretic peptide (ANP, BNP), as well as vasoconstrictor peptides like angiotensin and endothelin. 1 In the human myocardial interstitium, NEP represents the major bradykinin degrading enzyme. 2 Along with the renin-angiotensin system (RAS) and the sympathetic nervous system, the kallikrein-kinin system is involved in the onset and progression of heart failure and ventricular remodeling after myocardial infarction. 3 Kinins reduce left ventricular hypertrophy and fibrosis and prevent progression of heart failure. 3 Knockout of the predominant kinin receptor, the B 2 receptor, in mice leads to cardiac hypertrophy and heart failure. 4 In hypertensive rats, NEP inhibitors led to urinary kinin accumulation and natriuresis, and prevented cardiac hypertrophy and fibrosis. 5 Therefore, in addition to the RAS, NEP may represent a determinant of cardiac hypertrophy and fibrosis. Conclusions-ElevatedWe recently described an upregulation of myocardial angiotensin converting enzyme (ACE) mRNA and activity in patients with ventricular hypertrophy caused by AS and in heart failure. 6 Much less is known about the effects of human cardiac diseases on the regulation of myocardial NEP. Therefore, we studied the mRNA expression, activity, and cellular localization of NEP in the myocardium of patients with chronic pressure overload due to aortic stenosis and in patients with heart failure due to dilated cardiomyopathy. Methods PatientsLeft ventricular myocardial samples from 19 patients with aortic valve stenosis (AS-I, LVEF 52Ϯ4%, aortic gradient 76Ϯ7 mm Hg), 14 patients with heart failure due to dilated cardiomyopathy (DCM-I, EF 25Ϯ4%), and 14 control subjects were analyzed for NEP mRNA content. In a second series, 8 new comparable patients with AS, 8 patients with DCM, and 10 control subjects were analyzed for NEP activity. Small tissue samples from patients with A...

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