Reduced expression of angiotensin I-converting enzyme in Caveolin-1 knockout mouse lungs

Abstract

Reduced lung capillary expression of angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, and of caveolin-1, an important regulator of endothelial cell signalling, has been demonstrated in various models of pulmonary arterial hypertension (PAH). We addressed the relationship between PAH and ACE expression in caveolin-1 knockout mice (Cav1 −/− ), which have moderate PAH. Tissue ACE activity was reduced by 50% in lungs from 3-month old Cav1 −/− mice compared to wild type (WT). A similar reduction in lung endothelial ACE expression was observed by measuring the lung uptake of 125 I-labeled monoclonal anti-ACE antibody and by quantitative immunohistochemistry. These alterations in ACE are limited to capillary segments of the pulmonary circulation. Functionally, the increase in pulmonary artery pressure (PAP) in response to ACE conversion of angiotensin I to angiotensin II in isolated, perfused mouse lungs was reduced significantly in Cav1 −/− mice compared to WT. Thus, these complementary approaches demonstrate the dependence of lung microvascular endothelial cell ACE protein expression on caveolin-1 expression and underscore the vital role of caveolin-1-regulated pulmonary vascular homeostasis on endothelial ACE expression and activity. In summary, we have revealed a novel role of caveolin-1 in the regulation of ACE expression in pulmonary capillary endothelial cells. Further understanding of the mechanism by which reduced caveolin-1 expression leads altered pulmonary vascular development, PAH, and reduced ACE expression may have important clinical implications in patients with these severe lung diseases.

The ontogeny of human pulmonary angiotensin‐converting enzyme and its aberrant expression may contribute to the pathobiology of bronchopulmonary dysplasia (BPD)

“…19 It is also possible that ACE expression is linked to Caveolin 1, since mice deficient in Caveolin 1 develop abnormal microvasculature and pulmonary hypertension, and show reduced expression of pulmonary microvascular ACE. 24 Because of its high and rather specific ACE expression pulmonary microvasculature has been a unique and viable target to alter pulmonary endothelial functions in rodents. 25,26 Fetal rat lung ACE has been targeted to successfully diminish pulmonary diseases associated with congenital diaphragmatic hernia.…”

“…Altered blood flow has been suggested to potentially affect organogenesis . It is also possible that ACE expression is linked to Caveolin 1, since mice deficient in Caveolin 1 develop abnormal microvasculature and pulmonary hypertension, and show reduced expression of pulmonary microvascular ACE . Because of its high and rather specific ACE expression pulmonary microvasculature has been a unique and viable target to alter pulmonary endothelial functions in rodents .…”

“…Lung developmental case series was composed of paraffin-embedded human fetal autopsy lung tissues representing all three trimesters (12,13,16,18,24,34,39, and 40 weeks of gestational age (WGA)), as well as lung sections of 1 and 10 years old children with no significant lung pathology. The infant's gestational age was determined from the maternal last menstrual period or early prenatal ultrasound scans when available.…”

“…We studied pulmonary ACE expression during human lung development and in human bronchopulmonary dysplasia (BPD). Material and Methods: Human fetal autopsy lung tissue representing all three trimesters (12,13,16,18,24, 34, 39, and 40 weeks of gestational age (WGA)), as well as from 1 to 10 years of age with no significant lung pathology were used. In addition lung sections of patients with BPD (n ¼ 5) were selected.…”

Molecular regulation and clinical significance of caveolin‐1 methylation in chronic lung diseases

“…Deletion of Cav‐1 in mice also developed pulmonary hypertension, myocardial hypertrophy, and alveolar cell hyperproliferation through the activation of p42/44 MAP kinases 51 . Cav‐1 may regulate pulmonary vascular homeostasis through influencing endothelial angiotensin‐1 converting enzyme expression and activity, of which reduced expression of Cav‐1 leads to abnormal pulmonary vascular development 52 . COPD is a type of emphysema and/or chronic bronchitis characterized by airflow obstruction.…”