The double face of miR-320: cardiomyocytes-derived miR-320 deteriorated while fibroblasts-derived miR-320 protected against heart failure induced by transverse aortic constriction

Abstract

MicroRNAs (miRNAs) are aberrantly expressed in the pathophysiologic process of heart failure (HF). However, the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported, which might be covered by the globe effects of it on the heart. In the current study, Langendorff system was applied to isolate cardiomyocytes (CMs) and cardiac fibroblasts (CFs) from transverse aortic constriction (TAC)-induced mice. Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice. Interestingly, miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points. Then, recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo. Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction, whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy. Mechanically, downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs, respectively. Moreover, miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs. Interestingly, miR-320 treated CFs were able to indirectly affect CMs function, but not vice versa. Meanwhile, upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2, which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs, respectively. Together, we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.

Expression Profiles and Potential Functions of Long Non-Coding RNAs in the Heart of Mice With Coxsackie B3 Virus-Induced Myocarditis

“…A similar finding was also reported in our previous study. MiR-320 levels were significantly elevated in cardiomyocytes but were decreased in cardiac fibroblasts, thereby leading to a slight increase in miR-320 expression in the global heart tissue of TAC mice ( Zhang et al., 2021 ). Moreover, another study showed a decreased expression trend in SARS-CoV-2-infected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, as detected by RNA-seq ( Sharma et al., 2020 ).…”

A Non-Canonical Link between Non-Coding RNAs and Cardiovascular Diseases

“…As an example, sdRNA-93 and sno-miR-28 regulate cell proliferation by repressing the p53-stabilizing transcription initiation factor TFIID subunit 9b (TAF9B) [ 88 , 89 , 90 ]. MiR-320 is dysregulated in ischemic hearts, where its inhibition using anti-miR-320 reduces cardiac infarction size [ 91 ]. Moreover, it is highly expressed in the pancreatic islets of Langerhans, where it suppresses insulin resistance.…”

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease

“…Upon hyperglycemia, cardiomyocyte-derived exosomes are enriched in miR-320 which inhibits endothelial cell proliferation and perpetuates cell dysfunction in the onset of diabetes-associated cardiomyopathy [142]. Cardiac remodeling and fibrosis can also be associated to exosomal non-coding RNAs in cardiomyopathy.…”