Like other organs, the heart undergoes normal adaptive remodeling, such as cardiac hypertrophy, with age. This remodeling, however, is intensified under stress and pathological conditions. Cardiac remodeling could be beneficial for a short period of time, to maintain a normal cardiac output in times of need; however, chronic cardiac hypertrophy may lead to heart failure and death. MicroRNAs (miRNAs) are known to have a role in the regulation of cardiac hypertrophy. This paper reviews recent advances in the field of miRNAs and cardiac hypertrophy, highlighting the latest findings for targeted genes and involved signaling pathways. By targeting pro-hypertrophic genes and signaling pathways, some of these miRNAs alleviate cardiac hypertrophy, while others enhance it. Therefore, miRNAs represent very promising potential pharmacotherapeutic targets for the management and treatment of cardiac hypertrophy.

https://www.mdpi.com/1422-0067/20/19/4714/pdf

MicroRNAs in Cardiac Hypertrophy.

Aim Although miR-29 has emerged as a crucial non-coding RNA in the regulation of pathological cardiac hypertrophy, further exploration of its specific mechanisms is necessary to resolve controversy about its major role in this condition. This study therefore evaluated the role of miR-29a and whether it acts through the PTEN/AKT/mTOR pathway. Methods In this study, a rat model of pressure-induced cardiac hypertrophy was established by transverse aortic constriction and verified by echocardiography, histological analysis and quantitative RT-PCR. At the cellular level, we explored the role of miR-29a in angiotensin II-stimulated hypertrophic H9c2 cardiomyoblasts by transfecting the cells with miR-29a inhibitor and mimic. The relationship between miR-29a and the signalling pathway was investigated with dual luciferase reporter assays, immunofluorescence analysis and Western blotting. We also examined whether autophagy is involved in the regulatory mechanism of miR-29a through transmission electron microscopy and detection of autophagy-associated proteins. Results The results showed that miR-29a was upregulated both in rats 4 weeks after surgery and in 10-6 M angiotensin II-stimulated cells. In contrast, inhibition of miR-29a partially attenuated angiotensin II-induced hypertrophy. Additionally, bioinformatics analysis revealed that PTEN was one of the target genes of miR-29a, which was also verified by luciferase assay. The results of immunofluorescence and Western blotting indicated that overexpression of miR-29a inhibited the expression of PTEN, activated the AKT/mTOR pathway and suppressed autophagy, which ultimately led to cardiac hypertrophy. Conclusion In pathological cardiac hypertrophy, miR-29a was overexpressed and promoted cardiac hypertrophy by regulating the PTEN/AKT/mTOR pathway and suppressing autophagy.

miR‐29a promotes pathological cardiac hypertrophy by targeting the PTEN/AKT/mTOR signalling pathway and suppressing autophagy

MicroRNAs are small noncoding RNAs that can bind to the target sites in the 3'-untranslated region of messenger RNA to regulate posttranscriptional gene expression. Increasing evidence has identified the miR-29 family, consisting of miR-29a, miR-29b-1, miR-29b-2, and miR-29c, as key regulators of a number of biological processes. Moreover, their abnormal expression contributes to the etiology of numerous diseases. In the current review, we aimed to summarize the differential expression patterns and functional roles of the miR-29 family in the etiology of diseases including osteoarthritis, osteoporosis, cardiorenal, and immune disease. Furthermore, we highlight the therapeutic potential of targeting members of miR-29 family in these diseases. We present miR-29s as promoters of osteoblast differentiation and apoptosis but suppressors of chondrogenic and osteoclast differentiation, fibrosis, and T cell differentiation, with clear avenues for therapeutic manipulation. Further research will be crucial to identify the precise mechanism of miR-29 family in these diseases and their full potential in therapeutics.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.29896

The role of miR-29 family in disease

Circular RNA (circRNA) is a novel class of noncoding RNAs, and the roles of circRNAs in the development of cardiac hypertrophy remain to be explored. Here, we investigate the potential roles of circRNAs in cardiac hypertrophy. By circRNA sequencing in left ventricular specimens collected from 8-week-old mice with isoproterenol hydrochloride-induced cardiac hypertrophy, we found 401 out of 3323 total circRNAs were dysregulated in the hypertrophic hearts compared with the controls. Of these, 303 circRNAs were upregulated and 98 were downregulated. Moreover, the GO and KEGG analyses revealed that the majority of parental gene of differentially expressed circRNAs were not only related to biological process such as metabolic process and response to stimulus, but also related to pathway such as circulatory system and cardiovascular diseases. On the other hand, total 1974 miRNAs were predicted to binding to these differentially expressed circRNAs, and the possible target mRNAs of those miRNAs were also predicted and analyzed in terms of functional annotation. Finally, we identified that ANF and miR-23a are downstream targets of circRNA wwp1, suggesting that circRNA wwp1 exerts inhibitory roles of cardiac hypertrophy via down-regulation of ANF and miR-23a, which underlying the potential mechanisms whereby circRNA regulates cardiac hypertrophy.

Circular RNA expression in isoproterenol hydrochloride-induced cardiac hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Originally described as "orphan nuclear receptors", they can bind both natural and synthetic ligands acting as agonists or antagonists. In humans three subtypes, PPARα, β/δ, γ, are encoded by different genes, show tissue-specific expression patterns, and contribute to the regulation of lipid and carbohydrate metabolisms, of different cell functions, including proliferation, death, differentiation, and of processes, as inflammation, angiogenesis, immune response. The PPAR ability in increasing the expression of various antioxidant genes and decreasing the synthesis of pro-inflammatory mediators, makes them be considered among the most important regulators of the cellular response to oxidative stress conditions. Based on the multiplicity of physiological effects, PPAR involvement in cancer development and progression has attracted great scientific interest with the aim to describe changes occurring in their expression in cancer cells, and to investigate the correlation with some characteristics of cancer phenotype, including increased proliferation, decreased susceptibility to apoptosis, malignancy degree and onset of resistance to anticancer drugs. This review focuses on mechanisms underlying the antioxidant and anti-inflammatory properties of PPARs in physiological conditions, and on the reported beneficial effects of PPAR activation in cancer.

Peroxisome Proliferator-Activated Receptors (PPARs) and Oxidative Stress in Physiological Conditions and in Cancer

Although cardiac hypertrophy is widely recognized as a risk factor that leads to cardiac dysfunction and, ultimately, heart failure, the complex mechanisms underlying cardiac hypertrophy remain incompletely characterized. The nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) is involved in the regulation of cardiac lipid metabolism. Here, we describe a novel PPARδ-dependent molecular cascade involving microRNA-29a (miR-29a) and atrial natriuretic factor (ANF), which is reactivated in cardiac hypertrophy. In addition, we identify a novel role of miR-29a, in which it has a cardioprotective function in isoproterenol hydrochloride-induced cardiac hypertrophy by targeting PPARδ and downregulating ANF. Finally, we provide evidence that miR-29a reduces the isoproterenol hydrochloride-induced cardiac hypertrophy response, thereby underlining the potential clinical relevance of miR-29a in which it may serve as a potent therapeutic target for heart hypertrophy treatment.

Zhi-Feng Fu

Papers

miR‐29a attenuates cardiac hypertrophy through inhibition of PPARδ expression