p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1

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.G.S. is a YIP EMBO member. B.G.T. was a fellow of the FPI Severo Ochoa CNIC program (SVP-2013-067639) and currently is funded by the AHA-CHF (AHA award number: 818798). V.M.R. is a FPI fellow (BES-2014-069332) and A.M.S. is a fellow of the FPI Severo Ochoa CNIC program (BES-2016-077635). This work was funded by the following grants: to G.S.: funding from the EFSD/Lilly European Diabetes Research Programme Dr Sabio, from Spanish Ministry of Science, Innovation and Universities (MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00), Comunidad de Madrid (IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733) and Fundación Jesús Serra; to P.A.: Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971-16 to P.A.), MCIU/AEI/FEDER, funding from Spanish Ministry of Science, Innovation and Universities (RTI2018-095134-B-100); Excellence Network Grant from MICIU/AEI (SAF2016-81975-REDT and 2018-PN188) to PA and GS; to J.V.: funding from Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 (PT17/0019/0003- ISCIII-SGEFI / ERDF, ProteoRed), and “la Caixa” Banking Foundation (project code HR17-00247); to J.P.B.: funding from Spanish Ministry of Science, Innovation and Universities (PID2019-105699RB-I00, RED2018‐102576‐T) and Escalera de Excelencia (CLU-2017-03); to J.A.E.: funding from Spanish Ministry of Science, Innovation and Universities MINECO (RED2018-102576-T, RTI2018-099357-B-I00), CIBERFES (CB16/10/00282), and HFSP (RGP0016/2018). RAP (XPC/BBV1602 and MIN/RYC1102). The CNIC is supported by the Ministry of Science, Innovation and Universities and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury

A network of macrophages supports mitochondrial homeostasis in the heart

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte’s autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function

β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes

Selective stimulation of β3 adrenergic-receptor (β3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of β3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the β3AR agonist BRL37344 (5 μg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in β3AR agonist-treated mice. Incubation with β3AR agonist (BRL37344, 7 μmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 μg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of β3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes.S

Comparison of 1-year outcome in patients with severe aorta stenosis treated conservatively or by aortic valve replacement or by percutaneous transcatheter aortic valve implantation (data from a multicenter Spanish registry)

The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 ± 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies