Sabio lab

at the CNIO

Tag: heart (Page 3 of 7)

p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia

28/11/2023 /

Rafael Romero-Becerra, Francisco M. Cruz, Alfonso Mora, Juan Antonio Lopez, Daniela Ponce-Balbuena, Andrew Allan, Roberto Ramos-Mondragón, Bárbara González-Terán, Marta León, Maria Elena Rodríguez, Luis Leiva-Vega, Guadalupe Guerrero-Serna, Eric N. Jimenez-Vazquez, David Filgueiras-Rama, Jesús Vázquez, José Jalife & Guadalupe Sabio.

Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions.

Heart depolarizations recorded by optical membrane potential (Imagen: Rafael Romero-Becerra).

Here we found that the stress kinases p38γ and p38δ are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that, upon activation, p38γ and p38δ cooperatively increase the susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38γ and p38δ phosphorylate ryanodine receptor 2 (RyR2) disrupt Kv4.3 channel localization, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes and enhanced susceptibility to VF. Blocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals.

These results indicate that p38γ and p38δ are a potential therapeutic target for sustained VF prevention.

Nat Cardiovasc Res. 2023; doi: 10.1038/s44161-023-00368-x.

Programa CICERONE 2023 para estudiantes de Grado y Máster

29/03/2023 /

Como en años anteriores, nuestro grupo ofrece dos plazas para que estudiantes de Grado y Máster realicen prácticas en nuestro laboratorio entre el 1 de julio y el 15 de septiembre de 2023.

El propósito del programa CICERONE es acercar la investigación biomédica a los estudiantes universitarios para que puedan escoger más adecuadamente su orientación profesional.

Para inscribirse es necesario crear una cuenta en la web del CNIC antes del 28 de abril de 2023.

Enlace Tamaño
Bases de la convocatoria 2023 243 KB
Extracto del BOE 167 KB



Los dos proyectos científicos que ofrecemos este año son:

  • Stress in the brain, metabolic effects: Obesity has become a new pandemic. It is known that obesity induces molecular changes in the brain that are fundamental for the development of diseases and for maintaining excess energy intake. However, little is known about how these changes appear and the molecular mechanisms that mediate them. We will study how modulating stress in the central nervous system induced by high fat diet affects the development of cardiometabolic diseases. For this purpose, genetically modified animals will be used and whole organism metabolism will be evaluated, and how the signalling of this stress in the brain affects the response of distant organs through inter-tissue communication.
  • Role of adipose tissue controling whole body homeostasis: Cardiometabolic diseases (CMDs)—e.g., diabetes, steatohepatitis, and cardiomyopathy— are the leading cause of death worldwide. Adipose tissue (AT) heterogeneity and dysfunction might be involved in the CMD pathogenesis. We have recently demonstrated that i) AT regulates whole-body metabolism independently of obesity and predisposes to hepatic cancer in mice and humans; and ii) molecules secreted by AT trigger liver steatosis and insulin resistance. Our studies suggest that dysfunctional AT communicates with other organs and induces pathogenic adaptive responses through evolutionarily conserved mechanisms (rodent to humans). Our preliminary results show that AT dysfunction caused by mitochondrial alteration induces cardiomyopathy in lean mice, reinforcing that AT has a central role in controlling heart functionality.

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

17/08/2022 /

Rafael Romero-Becerra, Alfonso Mora, Elisa Manieri, Ivana Nikolic, Ayelén Melina Santamans, Valle Montalvo-Romeral, Francisco Miguel Cruz, Elena Rodríguez, Marta León, Luis Leiva-Vega, Laura Sanz, Víctor Bondía, David Filgueiras-Rama, Luis Jesús Jiménez-Borreguero, José Jalife, Barbara Gonzalez-Teran & Guadalupe Sabio.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6.

Cardiac hypertrophy under the microscope.
Cardiac hypertrophy in a heart lacking MKK6 (Image: Bárbara González-Terán).

Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin.

In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

eLife 2022; 11: e75250.

« Older posts Newer posts »

Fundación Princesa de Girona

Asociación Española Contra el Cáncer

Fundación BBVA

European Foundation for the Study of Diabetes

Immunothercan

© 2024 Sabio lab

Theme by Anders Norén — Up ↑