An Intronic Enhancer Element Regulates Angiotensin II Type 2 Receptor Expression during Satellite Cell Differentiation, and Its Activity Is Suppressed in Congestive Heart Failure

Abstract

Patients with advanced congestive heart failure (CHF) or chronic kidney disease often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II, via its type 1 receptor, causes muscle protein breakdown and apoptosis and inhibits satellite cell (SC) proliferation and muscle regeneration, likely contributing to cachexia in CHF and chronic kidney disease. In contrast, Ang II, via its type 2 receptor (AT2R) expression, is robustly induced during SC differentiation, and it potentiates muscle regeneration. To understand the mechanisms regulating AT2R expression and its potential role in muscle regeneration in chronic diseases, we used a mouse model of CHF and found that muscle regeneration was markedly reduced and that this was accompanied by blunted increase of AT2R expression. We performed AT2R promoter reporter analysis during satellite cell differentiation and found that the 70 bp upstream of the AT2R transcription start site contain a core promoter region, and regions upstream of 70 bp to 3 kbp are dispensable for AT2R induction. Instead, AT2R intron 2 acts as a transcriptional enhancer during SC differentiation. Further deletion/mutation analysis revealed that multiple transcription factor binding sites in the +286/+690 region within intron 2 coordinately regulate AT2R transcription. Importantly, +286/+690 enhancer activity was suppressed in CHF mouse skeletal muscle, suggesting that AT2R expression is suppressed in CHF via inhibition of AT2R intronic enhancer activity, leading to lowered muscle regeneration. Thus targeting intron 2 enhancer element could lead to the development of a novel intervention to increase AT2R expression in SCs and potentiate skeletal muscle regenerative capacity in chronic diseases.

Role of Vitamin D in Cardiovascular Diseases

“…Though the beneficial effect of AT1R is well established in treating HTN, HF, atherosclerosis, and aortic aneurysms, the beneficial effect of AT2R is under investigation [133–134]. The beneficial role of the AT2R agonist, Compound 21, in diabetes-associated atherosclerosis [135] and increased AT2R expression by targeting intron 2 enhancer element to increase satellite cell proliferation and potentiating skeletal muscle regenerative capacity in CHF patient has been discussed [136]. However, the protective role of AT2R, the underlying mechanism and interaction with vitamin D levels in CVD warrant further investigation.…”

Altered satellite cell dynamics accompany skeletal muscle atrophy during chronic illness, disuse, and aging

“…Recently, Yoshida et al . showed that angiotensin type 1 and 2 receptors (AT1R, AT2R) regulate different stages of satellite cell proliferation and activation (15**). In a mouse model of CHF, there was a marked reduction in muscle regeneration that was associated with attenuated AT2R expression (15**).…”

“…showed that angiotensin type 1 and 2 receptors (AT1R, AT2R) regulate different stages of satellite cell proliferation and activation (15**). In a mouse model of CHF, there was a marked reduction in muscle regeneration that was associated with attenuated AT2R expression (15**). Eloquent promoter reporter analysis experiments identified intron 2 of AT2R as a transcriptional enhancer element that promotes satellite cell differentiation.…”

“…Eloquent promoter reporter analysis experiments identified intron 2 of AT2R as a transcriptional enhancer element that promotes satellite cell differentiation. CHF however, suppressed the AT2R intron 2 enhancer activity, leading to diminished AT2R expression that likely contributes to impaired satellite cell differentiation and muscle regeneration (15**). Altered AT2R expression may also occur in other chronic conditions (chronic obstructive pulmonary disease, chronic kidney disease, etc.)…”

Neuro-Humoral Disbalance in Chronic Heart Failure: Classic and Modern Perspectives

“…Повыше-ние уровня A-II (циркулирующего, а также локальная концентрация A-II в узловом ганглии) наблюдается очень часто у пациентов с CH или хронической бо лезнью почек [6], при этом, A-II через рецептор 1 типа вызывает разрушение и апоптоз мышечного белка и ингибирует пролиферацию и регенерацию клеток-сателлитов, что, вероятно, способствует кахек-сии при ХСН и хронических заболеваниях почек. Напротив, экспрессия рецептора типа 2 (AT2R) инду-цируется во время дифференцировки клеток-сателли-тов и это потенцирует регенерацию мышц [7].…”