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Cardiac Senescence Is Associated with Enhanced Expression of Angiotensin II Receptor Subtypes¹

INSERM U127 (C.H., J.-S.S., F.M., B.C., B.S., J.-L.S.), INSERM U141 (B.I.L.), IFR Circulation, Hôpital Lariboisière, 75475 Paris Cedex 10, France, INSERM U36 (C.L.-C.), Collège de France, 75475 Paris Cedex 5, France

Address all correspondence and requests for reprints to: Dr. Jane-Lise Samuel, INSERM U127, IFR Circulation, Hôpital Lariboisière, 41 bd de la Chapelle, 75475 Paris Cedex 10, France.

Recent studies have pointed out the differential role of angiotensin II (Ang II) receptor subtypes, AT₁ and AT₂, in cardiac hypertrophy and fibrosis during pathological cardiac growth. Because senescence is characterized by an important cardiovascular remodeling, we examined the age-related expression of cardiac Ang II receptors in rats.

AT₁ and AT₂ receptor subtype messenger RNA (mRNA) levels were quantitated by RT-PCR. In parallel, specific Ang II densities were determined in competition binding experiments using specific antagonists. AT_1a and AT_1b mRNA levels were markedly up-regulated (5.6-fold) in the left ventricle of 24-month-old rats compared with 3-month-old rats, but not in the right ventricle. In contrast, AT₂ gene expression was increased in both ventricles of senescent rats (4.2- and 2.8-fold in the left and right ventricles, respectively). Similarly, AT₁ and AT₂ gene expression was increased 2.3- and 2-fold, respectively, in freshly isolated cardiomyocytes from aged rats. Furthermore, AT₁ and AT₂ specific binding was increased in the aged left ventricular myocardium.

Even though the mechanistic pathway of this up-regulation of Ang II receptor subtype gene expression might be intrinsic to developmental gene reprogramming, the up-regulation of AT₁ mRNA accumulation in the left ventricle during aging could also be secondary to age-related hemodynamic changes, whereas increased AT₂ gene expression in both ventricles may depend upon hormonal and humoral factors.

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