Molecular Regulation of Heart Failure
Heart Failure, a devastating condition with very high prevalence
Our lab studies the molecular mechanisms that regulate the development of heart failure. Heart failure is the ultimate consequence of heart disease and it basically represents the inability of the heart to pump blood in an efficient manner due to the lack of proper heart contraction or relaxation. He have a strong interest in heart failure with preserved ejection fraction (HFpEF), which is characterised by relaxation defects and accounts for half of the heart failure cases worldwide. There is no effective treatment for HFpEF and it is difficult to diagnose accurately. In our lab, we have developed translational mouse models that develop HFpEF naturally with old age and we are using them to explore novel biomarkers, investigate the underlying molecular mechanisms and test new therapeutic approaches.
Genetic cardiomyopathies, a truly translational story
A few years ago, Dr. Pablo García-Pavía came to us with a family that had a genetic cardiomyopathy due to a mutation in the gene TMEM43. This disease goes by the very attractive name of arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). There is no cure for this condition. Determined to find a solution for this disease, Dr. García-Pavía’s lab and ours joined forces and we established a truly translational collaboration from clinics to basic research and back again. We created a mouse model that expressed the human mutant protein and unveiled the pathological mechanism of the disease. We are now using this model as a platform to develop new therapies for this incurable disease, including gene therapy and drugs that are already approved in humans for other cardiac conditions. This fruitful collaboration has continued to grow and now expands into additional genetic cardiomyopathies. Our partnership includes joint papers in animal models and human patients, joint grants, common retreats, clinical researchers working at CNIC for a while and basic researchers familiarising with the work at the hospital, and other activities aimed at strengthening our bonds in order to bring therapeutic solutions to genetic cardiomyopathies, making this one of the most interesting and rewarding projects we have worked on. Our interest in cardiomyopathies now includes collaborators in other cities and countries, including a European network (DCM-NXET) focused on the study of the genetic and molecular mechanisms of dilated cardiomyopathy.
Figure 1. Mutation p.S358L in TMEM43 induces byventricular dysfunction and accumulation of fibrofatty tissue in the myocardium. Wt, wild type mice; TMEM43wt, mice overexpressing the wild type version of human TMEM43 in cardiomyocytes; TMEM43mut, mice expressing the mutant version of human TMEM43 in cardiomyocytes. Full paper here.
The many roles of RNA-binding proteins
Another of our main research interests is post-transcriptional regulation by RNA-binding proteins (RBPs). We have various ongoing projects investigating the role of different RBPs in heart disease using a combination of bioinformatic analysis, advanced molecular biology and animal models. In this context, we have recently reported that the regulatory axis composed by SRSF4 (an RBP), GAS5 (a non-coding mRNA) and GR (a transcription factor) controls cardiac hypertrophy and diastolic function. In contrast, the loss of SRSF3 in mouse hearts results in severe contraction defects due to alternative splicing of the master metabolic regulator mTOR. Alternative splicing (AS) is the molecular process that removes introns from immature pre-mRNAs and links exons together in different combinations. This mechanism affects 86% of all human genes and is in part responsible for the great diversity of proteins that are generated from the relatively small number of genes found in the human genome. During the last few years we have developed different bioinformatic tools to study AS and its regulation by RNA binding proteins (RBPs): dSreg, ATtRACT and FineSplice.Figure 2. Regulation of the serine and one-carbon metabolic pathway by the calcineurin A splicing variant CnAβ1. Whereas the CnAβ2 variant activates the transcription factor NFAT and induces pathological hypertrophy, CnAβ1, which is produced from the same gene by alternative splicing, activates the transcription factor ATF4, which triggers the Ser and one-carbon pathway. Activation of this pathway results in reduced mitochondrial protein oxidation, preserved ATP production, improved cardiac function and reduced pathological cardiac remodelling. For more information, please see our paper.
Calcineurin A beta1, one of our first projects that never stops surprising us
A good example of how alternative splicing can dramatically change protein function is the calcineurin variant CnAβ1. Calcineurin regulates a wide variety of physiological and pathological processes, including cardiac development and hypertrophy. CnAβ1 is a naturally occurring splice variant of the calcineurin A gene that contains a unique C-terminal region, which confers CnAβ1 specific properties. In a recent paper, we have shown that CnAβ1 improves cardiac function following myocardial infarction or aortic stenosis by activating the serine and one-carbon metabolic pathway, and thereby reducing oxidative damage in the mitochondria. We are now investigating how CnAβ1 regulates obesity by modulating fat deposits in white adipose tissue.
Figure 3. The RNA-binding protein SRSF4 regulates cardiac hypertrophy by controlling the stability of the non-coding RNA GAS5, which in turn inhibits the glucocorticoid receptor. Loss of SRSF4 in cardiomyocytes results in cardiac hypertrophy and diastolic dysfunction. Full paper here.
Obsessed with echocardiography
Additionally, we have a strong interest in the development of new models and methods to study the development of heart failure. We recently developed the first echography method to determine congestive heart failure in mice non-invasively (MoLUS) by using a combination of echocardiography and lung ultrasound and we have published guidelines on the non-invasive assessment of HFpEF. We are now taking advantage of these methods to search for biomarkers that can predict heart failure decompensation. We apply our echocardiography protocols to all the project we develop in the lab.
Video 1. Expression of TMEM43 with the p.S358L mutation results in severe cardiac contraction. The video shows echocardiographic images of the left ventricle in the longitudinal axis (please note the resolution of the video has been reduced). Wt, wild type mice; TMEM43wt, mice overexpressing the wild type version of human TMEM43 in cardiomyocytes; TMEM43mut, mice expressing the mutant version of human TMEM43 in cardiomyocytes. Full paper here.
All our work is carried out in a friendly atmosphere in the laboratory and in collaboration with different teams of clinicians, pharmacologists and biologists in different international and national institutions, and strongly supported by the different technical units at the CNIC.