Cardiovascular diseases and specifically heart failure (HF) impact global health and impose a significant economic burden on society. Despite current advances in standard of care, the risks for death and readmission of HF patients remain unacceptably high and new therapeutic strategies to limit HF progression are highly sought. In disease settings, persistent mechanical or neurohormonal stress to the myocardium triggers maladaptive cardiac remodeling, which alters cardiac function and structure at both the molecular and cellular level. The progression and magnitude of maladaptive cardiac remodeling ultimately leads to the development of HF. Classical therapies for HF are largely protein-based and mostly are targeted to ameliorate the dysregulation of neuroendocrine pathways and halt averse remodeling. More recently, investigation of novel molecular targets and the application of cellular therapies, epigenetic modifications, and regulatory RNAs has uncovered promising new avenues to address HF. In this review we summarize the current knowledge on novel cellular and epigenetic therapies and focus on two non-coding RNA-based strategies that reached the phase of early clinical development to counteract cardiac remodeling and HF. The current status of the development of translating those novel therapies to clinical practice, limitations and future perspectives are additionally discussed.

Emerging epigenetic therapies of cardiac fibrosis and remodeling in heart failure: from basic mechanisms to early clinical development.

Key regulatory miRNAs in lipid homeostasis: implications for cardiometabolic diseases and development of novel therapeutics.

For the past two decades since their discovery, scientists have linked microRNAs (miRNAs) to posttranscriptional regulation of gene expression in critical cardiac physiological and pathological processes. Multiple non-coding RNA species regulate cardiac muscle phenotypes to stabilize cardiac homeostasis. Different cardiac pathological conditions, including arrhythmia, myocardial infarction, and hypertrophy, are modulated by non-coding RNAs in response to stress or other pathological conditions. Besides, miRNAs are implicated in several modulatory signaling pathways of cardiovascular disorders including mitogen-activated protein kinase, nuclear factor kappa beta, protein kinase B (AKT), NOD-like receptor family pyrin domain-containing 3 (NLRP3), Jun N-terminal kinases (JNKs), Toll-like receptors (TLRs) and apoptotic protease-activating factor 1 (Apaf-1)/caspases. This review highlights the potential role of miRNAs as therapeutic targets and updates our understanding of their roles in the processes underlying pathogenic phenotypes of cardiac muscle. 

The potential role of miRNAs in the pathogenesis of cardiovascular diseases - A focus on signaling pathways interplay.

MicroRNAs in hypertrophic cardiomyopathy: pathogenesis, diagnosis, treatment potential and roles as clinical biomarkers

Tanshinone IIA (TAN) is widely employed for handling cardiovascular disorders. The current study explored the potential role of miRs in the antifibrotic effect of TAN on heart. Fibrotic features were induced in cardiac fibroblasts (CFs) and in rat hearts, and then handled with TAN. MicroRNAs (miRs) responding to TAN were determined using a microarray assay. The selected miR was modulated to verify its role in antifibrotic effects of TAN. TAN suppressed the viability and the production of α-SMA in CFs, which was associated with 101 miR being upregulated and 223 miR being downregulated. MiR-618 was selected as the potential target of TAN. Ang II inhibited miR-618 level and resulted in the upregulation of pro-fibrosis factors, which was reversed by TAN. The antifibrotic effect of TAN was weakened by miR-618 inhibition. TAN inhibits hypertrophy and collagen deposition in heart tissues, which is associated with the increased level of miR-618. PRACTICAL APPLICATIONS: The findings outlined in the current study show that the antifibrotic function of TAN is closely related to the function of miRs: the induction of miR-618 is indispensable for the function of TAN against the fibrotic process after heart injury, which will promote the application of TAN as an adjuvant therapy for improving heart function.

Tanshinone IIA from Salvia miltiorrhiza exerts anti-fibrotic effects on cardiac fibroblasts and rat heart tissues by suppressing the levels of pro-fibrotic factors: The key role of miR-618.

Heart failure (HF) describes a group of manifestations caused by the failure of heart function as a pump that supports blood flow through the body. MicroRNAs (miRNAs), as one type of non-coding RNA molecule, have crucial roles in the etiology of HF. Accordingly, miRNAs related to HF may represent potential novel therapeutic targets. In this review, we first discuss the different roles of miRNAs in the development and diseases of the heart. We then outline commonly used miRNA chemical modifications and delivery systems. Further, we summarize the opportunities and challenges for HF-related miRNA therapeutics targets, and discuss the first clinical trial of an antisense drug (CDR132L) in patients with HF. Finally, we outline current and future challenges and potential new directions for miRNA-based therapeutics for HF.

Huatao Zhou

Papers

MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure