Search

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.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the human population, with an estimated incidence of 1–2% in young adults but increasing to more than 10% in 80+ years patients. Pituitary Homeobox 2, Paired Like Homeodomain 2 (PITX2c) loss-of-function in mice revealed that this homeodomain (HD)-containing transcription factor plays a pivotal role in atrial electrophysiology and calcium homeostasis and point to PITX2 as a candidate gene for AF. To address this issue, we recruited 31 AF patients for genetic analyses of both the known risk alleles and PITX2c open reading frame (ORF) re-sequencing. We found two-point mutations in the homedomain of PITX2 and three other variants in the 5’untranslated region. A 65 years old male patient without 4q25 risk variants but with recurrent AF displayed two distinct HD-mutations, NM_000325.5:c.309G>C (Gln103His) and NM_000325.5:c.370G>A (Glu124Lys), which both resulted in a change within a highly conserved amino acid position. To address the functional impact of the PITX2 HD mutations, we generated plasmid constructs with mutated version of each nucleotide variant (MD4 and MD5, respectively) as well as a dominant negative control construct in which the PITX2 HD was lacking (DN). Functional analyses demonstrated PITX2c MD4 and PITX2c MD5 decreased Nppa-luciferase transactivation by 50% and 40%, respectively, similar to the PITX2c DN (50%), while Shox2 promoter repression was also impaired. Co-transactivation with other cardiac-enriched co-factors, such as Gata4 and Nkx2.5, was similarly impaired, further supporting the pivotal role of these mutations for correct PITX2c function. Furthermore, when expressed in HL1 cardiomyocyte cultures, the PITX2 mutants impaired endogenous expression of calcium regulatory proteins and induced alterations in sarcoplasmic reticulum (SR) calcium accumulation. This favored alternating and irregular calcium transient amplitudes, causing deterioration of the beat-to-beat stability upon elevation of the stimulation frequency. Overall this data demonstrate that these novel PITX2c HD-mutations might be causative of atrial fibrillation in the carrier.

Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks