Molecular Regulation of Heart Failure
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.
One of our main interests is the role and regulation of alternative splicing (AS) in heart failure. 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 two bioinformatic tools to study AS and its regulation by RNA binding proteins (RBPs): FineSplice and ATtRACT. In addition, 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.
A good example of how alternative splicing can dramatically change protein function is the calcineurin variant CnAb1. Calcineurin regulates a wide variety of physiological and pathological processes, including cardiac development and hypertrophy. CnAb1 is a naturally occurring splice variant of the calcineurin A gene that contains a unique C-terminal region, which confers CnAβ1 specific properties. In recent papers, we have shown that CnAb1 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 also have a strong interest in the molecular mechanisms that mediate the development of different genetic cardiomyopathies. As part of a very fruitful long-lasting collaboration with the group of Dr. Pablo García-Pavía at the Hospital Puerta de Hierro in Majadahonda, we have unveiled the pathological mechanism of arrythmogenic cardiomypathy type 5 (ARVC5), which is caused by the p.S358L mutation in the TMEM43 gene. We have developed a mouse model that reproduces the human disease and we are now using this model as a platform to develop new therapies for this incurable and lethal disease.
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. We are now taking advantage of this method to seacrh for biomarkers that can predict heart failure decompensation.
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.