LncRNAs and CircRNAs in Endoplasmic Reticulum Stress: A Promising Target for Cardiovascular Disease?

The endoplasmic reticulum (ER) is a principal subcellular organelle responsible for protein quality control in the secretory pathway, preventing protein misfolding and aggregation. Failure of protein quality control in the ER triggers several molecular mechanisms such as ER-associated degradation (ERAD), the unfolded protein response (UPR) or reticulophagy, which are activated upon ER stress (ERS) to re-establish protein homeostasis by transcriptionally and translationally regulated complex signalling pathways. However, maintenance over time of ERS leads to apoptosis if such stress cannot be alleviated. The presence of abnormal protein aggregates results in loss of cardiomyocyte protein homeostasis, which in turn results in several cardiovascular diseases such as dilated cardiomyopathy (DCM) or myocardial infarction (MI). The influence of a non-coding genome in the maintenance of proper cardiomyocyte homeostasis has been widely proven. To date, the impact of microRNAs in molecular mechanisms orchestrating ER stress response has been widely described. However, the role of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) is just beginning to be addressed given the potential role of these RNA classes as therapeutic molecules. Here, we provide a current state-of-the-art review of the roles of distinct lncRNAs and circRNAs in the modulation of ERS and UPR and their impact in cardiovascular diseases.

LncRNA H19 Impairs Chemo and Radiotherapy in Tumorigenesis.

Various treatments based on drug administration and radiotherapy have been devoted to preventing, palliating, and defeating cancer, showing high efficiency against the progression of this disease. Recently, in this process, malignant cells have been found which are capable of triggering specific molecular mechanisms against current treatments, with negative consequences in the prognosis of the disease. It is therefore fundamental to understand the underlying mechanisms, including the genes-and their signaling pathway regulators-involved in the process, in order to fight tumor cells. Long non-coding RNAs, H19 in particular, have been revealed as powerful protective factors in various types of cancer. However, they have also evidenced their oncogenic role in multiple carcinomas, enhancing tumor cell proliferation, migration, and invasion. In this review, we analyze the role of lncRNA H19 impairing chemo and radiotherapy in tumorigenesis, including breast cancer, lung adenocarcinoma, glioma, and colorectal carcinoma.

Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis.

Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo. The precardiac mesoderm subsequently fused at the embryonic midline constituting an embryonic linear heart tube. As development progress, the embryonic heart displays the first sign of left-right asymmetric morphology by the invariably rightward looping of the initial heart tube and prospective embryonic ventricular and atrial chambers emerged. As cardiac development progresses, the atrial and ventricular chambers enlarged and distinct left and right compartments emerge as consequence of the formation of the interatrial and interventricular septa, respectively. The last steps of cardiac morphogenesis are represented by the completion of atrial and ventricular septation, resulting in the configuration of a double circuitry with distinct systemic and pulmonary chambers, each of them with distinct inlets and outlets connections. Over the last decade, our understanding of the contribution of multiple growth factor signaling cascades such as Tgf-beta, Bmp and Wnt signaling as well as of transcriptional regulators to cardiac morphogenesis have greatly enlarged. Recently, a novel layer of complexity has emerged with the discovery of non-coding RNAs, particularly microRNAs and lncRNAs. Herein, we provide a state-of-the-art review of the contribution of non-coding RNAs during cardiac development. microRNAs and lncRNAs have been reported to functional modulate all stages of cardiac morphogenesis, spanning from lateral plate mesoderm formation to outflow tract septation, by modulating major growth factor signaling pathways as well as those transcriptional regulators involved in cardiac development.