SCIENTIFIC REpORTS | 7: 16802 | DOI:10.1038/s41598-017-17103-9
The role of oxidative stress in
the crosstalk between leptin and
mineralocorticoid receptor in the
cardiac brosis associated with
, Gema Marín-Royo
, Ernesto Martínez-Martínez
, Rubén Martín
, Natalia López-Andrés
, Raquel Jurado-López
, Isabel Gallardo
, José Alberto San Román
, María González-Amor
, Mercedes Salaices
, María Luisa
& Victoria Cachofeiro
We have investigated whether mineralocorticoid receptor activation can participate in the probrotic
eects of leptin in cardiac myobroblasts, as well as the potential mechanisms involved. The presence
of eplerenone reduced the leptin-induced increase in protein levels of collagen I, transforming growth
factor β, connective tissue growth factor and galectin-3 and the levels of both total and mitochondrial
of superoxide anion (O
−) in cardiac myobroblasts. Likewise, the MEK/ERK inhibitor, PD98059, and
the PI3/Akt inhibitor, LY294002, showed a similar pattern. Mitochondrial reactive oxygen species (ROS)
scavenger (MitoTempo) attenuated the increase in body weight observed in rats fed a high fat diet
(HFD). No dierences were found in cardiac function or blood pressure among any group. However, the
cardiac brosis and enhanced O
-levels observed in HFD rats were attenuated by MitoTempo, which
also prevented the increased circulating leptin and aldosterone levels in HFD fed animals. This study
supports a role of mineralocorticoid receptor in the cardiac brosis induced by leptin in the context of
obesity and highlights the role of the mitochondrial ROS in this process.
Extracellular matrix (ECM) accumulation is a common response of the heart to dierent types of damage, includ-
ing obesity. e development of cardiovascular brosis has been repeatedly reported in obesity in experimental
and clinical studies, which is frequently accompanied by co-morbidities such as hypertension and diabetes that
can favour the development of cardiac brosis
. Growing evidence indicates that myocardial brosis is one of
the pivotal contributors to heart muscle dysfunction in obesity
. e excessive ECM deposit due to a large
number of myobroblasts, the cell mainly responsible for brosis, can cause an aberrant remodelling that favours
functional alterations, since a reduced relaxing capability of the heart can increase its lling pressure and contrib-
ute to diastolic dysfunction.
Multiple factors have been proposed as being responsible for the increased accumulation of collagen content
in the myocardium in the context of obesity, with leptin being one of these factors
. is adipokine is locally
Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid and Instituto de
Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
Cardiovascular Translational Research,
Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona,
Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain.
de Enfermería y Fisioterapia, Salus Inrmorum. Universidad Ponticia de Salamanca, Madrid, Spain.
Cardiología, Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain.
Instituto de Ciencias del Corazón
(ICICOR), Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
Departamento de Farmacología, Facultad
de Medicina, Universidad Autónoma de Madrid and Instituto de Investigación Hospital Universitario La Paz (IdiPAZ),
Ciber de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Madrid, Spain.
Josué Gutiérrez-Tenorio, Gema Marín-Royo, María Luisa Nieto and Victoria Cachofeiro contributed equally to this
work. Correspondence and requests for materials should be addressed to V.C. (email: firstname.lastname@example.org)
Received: 14 February 2017
Accepted: 22 November 2017
Published: xx xx xxxx