Researchers from the CIBER on Cardiovascular Diseases (CIBERCV) have analysed the contribution of a protein (the NOR-1 nuclear receptor) to the progression of hypertensive cardiac hypertrophy, thanks to the creation of a transgenic mouse model. In this way, they open a new way to discover new therapies to face this disease, which is the main cause of heart failure, one of the most important health problems of our society.
This work, published in the journal Clinical Science, has been led by CIBERCV researchers José Martínez González, from the Institute of Biomedical Research of Barcelona (IIBB-CSIC) and Cristina Rodríguez, from the Research Institute of the Hospital de la Santa Creu i Sant Pau – IIB Sant Pau, in collaboration with Leif Hove-Madsen (IIBB-CSIC) and Juan Francisco Nistal (Hospital Universitario Marqués de Valdecilla de Santander), also researchers from CIBERCV. In this study they have developed a model of a transgenic mouse that overexpresses human NOR-1 in the heart, demonstrating the relevant role in this disease.
As Cristina Rodríguez Sinovas explains, “these animals have a greater predisposition to cardiac remodelling associated with ageing and a greater susceptibility to develop cardiac hypertrophy induced by pressure overload, presenting greater hypertrophy of the cardiomyocyte, more inflammation and fibrosis”.
These results indicate that this transgenic mouse may be useful as a new animal model in preclinical studies of molecules with therapeutic potential against cardiac hypertrophy. “The molecular mechanisms underlying this disease are not fully understood, and the prevalence of heart failure is increasing worldwide, while effective treatments remain elusive. Therefore, it is of great interest to generate these models that will allow the development of new therapies to attack the pathological remodeling of the heart with the intention of preventing, stopping or reversing the progression of this disease,” says CIBERCV group leader José Martínez González.
Major remodeling associated with aging in the left ventricle of transgenic animals detected
The developed transgenic mice have overexpressed NOR-1 in the heart, mainly in cardiomyocytes, which experienced an increase in cell size, but also in cardiofibroblasts (more likely to synthesize collagen and migrate); and also have developed a greater remodeling associated with the aging of the left ventricle. “We determined that the NOR-1 receptor positively regulates two key genes involved in cardiac hypertrophy and fibrosis, so our findings suggest that this receptor is involved in the transcriptional program that leads to hypertensive cardiac hypertrophy,” says Dr. Martínez González.
One of the major public health problems in the world
Hypertensive cardiac hypertrophy (HCH) is a compensatory response of the heart to neurohormonal stress and hemodynamic overload (e.g. resulting from hypertension and valve disease) whose prolongation over time leads to congestive heart failure (CHF), the leading cause of hospitalization in the elderly and one of the world’s public health problems. According to recent studies, the prevalence of this disease doubles with each decade of age and is around 10% in those over 70. Control of risk factors, such as hypertension and ischemic heart disease, as well as unhealthy lifestyle habits, are the only means to control the expected increase of this disease in the future.
Today, the mechanisms underlying the molecular changes that lead to hypertensive cardiac hypertrophy are not fully understood, so this research has aimed to analyse them through the development of a new animal model.
The use of genetically modified animals in scientific research is essential to understand the diseases and to find possible therapies. These animal models are used under strict control to ensure that they are protected and their welfare is assured; and, in short, they help to cure diseases, improve quality of life and save human lives.
Reference article:
Neuron-derived orphan receptor-1 modulates cardiac gene expression and exacerbates angiotensin II-induced cardiac hypertrophy Laia Cañes, Ingrid Martí-Pàmies, Carme Ballester-Servera, Adela Herraiz-Martínez, Judith Alonso, María Galán, J Francisco Nistal, Pedro Muniesa, Jesús Osad, Leif Hove-Madsen, Cristina Rodríguez and José Martínez-González. https://www.ncbi.nlm.nih.gov/pubmed/31985010
