Dataset Information

The association between microRNA-21 and hypertension-induced cardiac remodeling.

ABSTRACT: Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-?1 (TGF-?1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-?1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-?1 signaling pathway.

SUBMITTER: Watanabe K

PROVIDER: S-EPMC7010249 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The association between microRNA-21 and hypertension-induced cardiac remodeling.

Watanabe Ken K Narumi Taro T Watanabe Tetsu T Otaki Yoichiro Y Takahashi Tetsuya T Aono Tomonori T Goto Jun J Toshima Taku T Sugai Takayuki T Wanezaki Masahiro M Kutsuzawa Daisuke D Kato Shigehiko S Tamura Harutoshi H Nishiyama Satoshi S Takahashi Hiroki H Arimoto Takanori T Shishido Tetsuro T Watanabe Masafumi M

PloS one 20200210 2

Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively cor ...[more]

PMID: 32040481

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Project description:Primary aldosteronism is characterized by excess aldosterone secretion by the adrenal gland independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess aldosterone causes cardiac hypertrophy, fibrosis, inflammation, and hypertension. The molecular mechanisms that trigger the onset and progression of aldosterone-mediated cardiac injury remain incompletely understood. MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that have been implicated in multiple cardiac pathologies; however, their regulation and role in aldosterone-mediated cardiac injury and dysfunction remains mostly unknown. We previously reported that microRNA-21 (miR-21) is the most upregulated miRNA by excess aldosterone in the left ventricle in a rat experimental model of primary aldosteronism. To elucidate the role of miR-21 in aldosterone-mediated cardiac injury and dysfunction, miR-21 knockout mice and their wild-type littermates were treated with aldosterone infusion and salt in the drinking water for 2 or 8 wk. miR-21 genetic ablation exacerbated aldosterone/salt-mediated cardiac hypertrophy and cardiomyocyte cross-sectional area. Furthermore, miR-21 genetic ablation increased the cardiac expression of fibrosis and inflammation markers and fetal gene program. miR-21 genetic ablation increased aldosterone/salt-mediated cardiac dysfunction but did not affect aldosterone/salt-mediated hypertension. miR-21 target gene Sprouty 2 may be implicated in the cardiac effects of miR-21 genetic ablation. Our study shows that miR-21 genetic ablation exacerbates aldosterone/salt-mediated cardiac hypertrophy, injury, and dysfunction blood pressure independently. These results suggest that miR-21 plays a protective role in the cardiac pathology triggered by excess aldosterone. Furthermore, miR-21 supplementation may be a novel therapeutic approach to abolish or mitigate excess aldosterone-mediated cardiovascular deleterious effects in primary aldosteronism.

Project description:BackgroundMechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses.Methodology/principal findingsWe employed ascending aortic stenosis (AS) and heterotopic heart transplantation (HTX) in syngenic Lewis rats to induce mechanical overloading and unloading, respectively. Heart weight was 26±3% higher in AS (n?=?7) and 33±2% lower in HTX (n?=?7) as compared to sham-operated (n?=?6) and healthy controls (n?=?7). Small RNAs were enriched from the left ventricles and subjected to quantitative stem-loop specific RT-PCR targeting a panel of 351 miRNAs. In total, 153 miRNAs could be unambiguously detected. Out of 72 miRNAs previously implicated in the cardiovascular system, 40 miRNAs were regulated in AS and/or HTX. Overall, HTX displayed a slightly broader activation pattern for moderately regulated miRNAs. Surprisingly, however, the regulation of individual miRNA expression was strikingly similar in direction and amplitude in AS and HTX with no miRNA being regulated in opposite direction. In contrast, fetal hearts from Lewis rats at embryonic day 18 exhibited an entirely different miRNA expression pattern.ConclusionsTaken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern. The direction of postnatal adaptive cardiac growth does, therefore, not appear to be determined at the level of single miRNAs or a specific set of miRNAs. Moreover, miRNAs themselves are not reprogrammed to a fetal program in response to changes in hemodynamic load.

Dataset Information

The association between microRNA-21 and hypertension-induced cardiac remodeling.

Publications

The association between microRNA-21 and hypertension-induced cardiac remodeling.

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