Glucocorticoids Suppress Growth in Neonatal Cardiomyocytes Co-Expressing AT₂ and AT₁ Angiotensin Receptors

Abstract

Background: Perinatal glucocorticoid treatment is associated with hypertrophic cardiomyopathy, but the cellular mechanism is controversial. An underlying interaction between glucocorticoids and the renin-angiotensin system may be important, but whether glucocorticoids modulate angiotensin II (AngII)-dependent cardiomyocyte growth responses in the neonate has not been investigated. Objectives: The major aim of this investigation was to determine whether glucocorticoids modulate the neonatal cardiomyocyte growth response to AngII. In particular we sought evidence to determine whether angiotensin II type 2 (AT₂) receptor co-expression with angiotensin II type 1 (AT₁) receptor is of specific importance in this modulatory function. Methods: In this study, we used AT₁ and AT₂ receptor-expressing adenoviruses (Ad-AT₁ and Ad-AT₂) in a well-defined in vitro neonatal cardiomyocyte culture model to assess whether glucocorticoids affect cardiomyocyte growth responses (i.e. total protein content). Results: Following addition of AngII (0.1 µmol/l) to neonatal cardiomyocytes infected with Ad-AT₁ alone, a significant growth response was measured (133.2 ± 4.8%). Expression of Ad-AT₂ alone induced a ∼20% increase in total cellular protein content, which was unaffected by addition of AngII. Neither corticosterone (1 µmol/l) nor dexamethasone (1 µmol/l) had any significant effect on the AT₁- or AT₂-mediated growth responses. In contrast, the growth response to AngII was augmented following co-expression of AT₂ and AT₁ receptors (149.2 ± 4.2%), which was reduced by ∼20% in the presence of either corticosterone or dexamethasone (p < 0.05). Conclusions: The present study provides novel evidence that glucocorticoids suppress neonatal cardiomyocyte growth responsiveness when AT₂and AT₁ receptor subtypes are co-expressed.

Proteomic Analysis of Morphologically Changed Tissues after Prolonged Dexamethasone Treatment

“…Involvement of the Akt signaling pathway in the heart tissue indicates the involvement of non-genomic actions of Dex in the development of side effects in the heart characterized by its reduced size compared to the controls. This can be related to the repressive effect of Dex on the proteins involved in the cell cycle [40] leading to suppression of the growth of cardiomyocytes [41] and a decrease in heart weight due to the inhibition of myocyte mitotic activity [30].…”

Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications

“…In neonates, complicated and sometimes contradictory accounts have also been noted. Studies have revealed that the glucocorticoid treatment is associated with hyperplasic [ 30 ], hypertrophic [ 31 , 32 ] or no effect on the growth [ 33 ] of cardiomyocytes, as analyzed by the protein to DNA ratio. Formation of binucleated myocardial cells is regarded as an early indicator of transition of hyperplasia to hypertrophic growth [ 10 ], indicating ceasing of proliferation of cardiomyocytes.…”

Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II

“…Its primary effector hormone, angiotensin II (Ang II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension and cardiac hypertrophy in a series of CVDs . Many studies support the observation that Ang II has direct effects on myocardial cells, including cardiomyocyte growth, accumulation of extracellular matrix and hypertrophy . These effects are known to be mediated by angiotensin type 1 receptor (AT1R), demonstrated by the fact that AT1R antagonists prevent Ang II‐induced cardiac hypertrophy in rats .…”