Álvaro Sahún-Español, Cristina Clemente, Juan Ignacio Jiménez-Loygorri, Elena Sierra-Filardi, Leticia Herrera-Melle, Aurora Gómez-Durán, Guadalupe Sabio, María Monsalve, Patricia Boya & Alicia G Arroyo.
Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players in this process.
We demonstrate that MT4-MMP absence boosted VSMC proliferation in vitro in response to PDGF-BB in a cell-autonomous manner through enhanced p38 MAPK activity. Increased phospho-p38 in basal MT4-MMP-null VSMCs augmented the rate of mitochondrial degradation by promoting mitochondrial morphological changes through the co-activator PGC1α as demonstrated in PGC1α−/− VSMCs. We tested the in vivo implications of this pathway in a novel conditional mouse line for selective MT4-MMP deletion in VSMCs and in mice pre-treated with the p38 MAPK activator anisomycin. Priming of p38 MAPK activity in vivo by the absence of the protease MT4-MMP or by anisomycin treatment led to enhanced arteriogenesis and improved flow recovery after femoral artery occlusion.
These findings may open new therapeutic opportunities for peripheral vascular diseases.
Elena Hernández-García, Francisco J. Cueto, Emma C. L. Cook, Ana Redondo-Urzainqui, Sara Charro-Zanca, Iñaki Robles-Vera, Ruth Conde-Garrosa, Ivana Nikolić, Guadalupe Sabio, David Sancho & Salvador Iborra.
Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear.
Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells.
These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.
Ayelén M. Santamans, Valle Montalvo-Romeral, Alfonso Mora, Juan Antonio Lopez, Francisco González-Romero, Daniel Jimenez-Blasco, Elena Rodríguez, Aránzazu Pintor-Chocano, Cristina Casanueva-Benítez, Rebeca Acín-Pérez, Luis Leiva-Vega, Jordi Duran, Joan J. Guinovart, Jesús Jiménez-Borreguero, José Antonio Enríquez, María Villlalba-Orero, Juan P. Bolaños, Patricia Aspichueta, Jesús Vázquez, Bárbara González-Terán, Guadalupe Sabio.
During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart.
We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation.
These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.