Angiotensin Converting Enzyme Inhibition Decreases Cell Turnover in the Neonatal Rat Heart

Abstract

The renin angiotensin system plays an important role in growth and development. Exposure of the neonate to an ACE inhibitor increases mortality and results in growth retardation and abnormal development. We have demonstrated that ACE inhibition in the developing kidney increases apoptosis and decreases cell proliferation, which may account for renal growth impairment. To evaluate the role of endogenous angiotensin in cardiac development, the relationship between ACE inhibition, cell proliferation, apoptosis, several modulators of apoptosis (bcl-2, bcl-xl, and clusterin) was examined in the developing rat heart. Thirty-five newborn rat pups were treated with enalapril (30 mg/kg/d) or a vehicle (control group) for 7 d, and hearts were removed for rt-PCR and Western blotting of bcl-2, bcl-xl, and clusterin. An additional 10 rat pups were treated with hydralazine (10 mg/kg/d) or a vehicle, to serve as a hypotensive control. Cell proliferation was determined by PCNA immunostaining, and apoptosis was detected using the total TUNEL technique. Enalapril treatment resulted in a 24% mortality, reduced body weight, and decreased heart weight (p < 0.05). Enalapril decreased proliferating myocytes by 23%, and reduced proliferating cardiac interstitial cells by 8.1% (p < 0.05). Enalapril also decreased myocytes apoptosis by 60%, but the proportion of myocytes undergoing apoptosis was 10-fold less than that of proliferating cells. Cardiac bcl-2 mRNA, clusterin mRNA, bcl-2 protein, and bcl-xl protein content were not changed, but clusterin protein expression was decreased by enalapril treatment. Hydralazine did not alter cardiac cell proliferation or apoptosis. We conclude that ACE inhibition decreases cell turnover in the developing rat heart, which may contribute to cardiac growth impairment. The loss of myocytes may lead to greater myocyte hypertrophy and myocardial damage during later life.

Effects of Glucocorticoid Exposure on Growth and Structural Maturation of the Heart of the Preterm Piglet

“…The higher levels of Ki-67 immunolabeling (a marker of cell cycle activity) and lower levels of caspase-3 immunolabeling (a marker of apoptosis) in preterm piglet hearts confirms that at 91 days gestation (equivalent to 25–27 weeks human gestation) the heart is growing by hyperplasia as well as hypertrophy, as seen in other species [12], [34], [35]. During the last weeks of pregnancy in the pig, however, there is evidence that this hyperplastic growth declines since the number of Ki-67 positive nuclei were less at term (Figure 4A), while hypertrophy continued as indicated by the increase in myocyte volume (Figure 2).…”

Aldosterone Modulates Cell Proliferation and Apoptosis in the Neonatal Rat Heart

“…In addition, angiotensin II promotes cell growth via angiotensin II type I (AT1) receptors in cardiac myocytes, which cause inotropic and chronotropic changes and induce apoptosis in myocytes (14). A number of studies have demonstrated that alterations in the RAAS of developing rats affect cardiac growth and development (1, 15). A recent new wave of interest in aldosterone physiology has been generated by its role in cardiovascular homeostasis including blood-pressure homeostasis, myocardial fibrosis and remodeling of blood vessels (6).…”

“…Our previous studies demonstrated that alterations in the renin angiotensin aldosterone system (RAAS), of the developing rat, affect cardiac and renal growth and development (1). To date, many studies have reported that RAAS plays a major role in the pathophysiology of the cardiovascular system (2, 3).…”

Endothelin A Receptor Blockade Influences Apoptosis and Cellular Proliferation in the Developing Rat Kidney

“…In our previous study, we demonstrated that Ang II modulates growth in a variety of tissues, including the kidney and the heart (7, 8, 12, 13). Ang II inhibition by angiotensin converting enzyme (ACE) inhibitor in the developing rat kidney decreases the cellular proliferation and increases apoptosis, and this may account for neonatal renal growth impairment (7, 8, 12-15).…”

“…Immunostaining was performed on paraffin sections as described previously (7, 8). The proliferating cell nuclear antigen (PCNA) cells and terminal deoxynucleotide transferase-mediated nick-end labeling (TUNEL)-positive apoptotic cells were detected using the avidin-biotin immunoperoxidase method (Vectastain ABC kit, Burlingame, CA, U.S.A.) and the TACS TM 2 TdT In Situ Apoptosis Detection Kit (Trevigen, Gaithersburg, MD, U.S.A.), respectively.…”