Circulating miR-320a as a Predictive Biomarker for Left Ventricular Remodelling in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention

Restoration of epicardial coronary blood flow, achieved by early reperfusion with primary percutaneous coronary intervention (PPCI), is the guideline recommended to treat patients with ST-segment-elevation myocardial infarction (STEMI). However, despite successful blood restoration, increasing numbers of patients develop left ventricular adverse remodelling (LVAR) and heart failure. Therefore, reliable prognostic biomarkers for LVAR in STEMI are urgently needed. Our aim was to investigate the role of circulating microRNAs (miRNAs) and their association with LVAR in STEMI patients following the PPCI procedure. We analysed the expression of circulating miRNAs in blood samples of 56 patients collected at admission and after revascularization (at 3, 6, 12 and 24 h). The associations between miRNAs and left ventricular end diastolic volumes at 6 months were estimated to detect LVAR. miRNAs were also analysed in samples isolated from peripheral blood mononuclear cells (PBMCs) and human myocardium of failing hearts. Kinetic analysis of miRNAs showed a fast time-dependent increase in miR-133a, miR-133b, miR-193b, miR-499, and miR-320a in STEMI patients compared to controls. Moreover, the expression of miR-29a, miR-29b, miR-324, miR-208, miR-423, miR-522, and miR-545 was differentially expressed even before PPCI in STEMI. Furthermore, the increase in circulating miR-320a and the decrease in its expression in PBMCs were significantly associated with LVAR and correlated with the expression of miR-320a in human failing myocardium from ischaemic origin. In conclusion, we determined the time course expression of new circulating miRNAs in patients with STEMI treated with PPCI and we showed that miR-320a was positively associated with LVAR

TRPC Channels: Dysregulation and Ca2+ Mishandling in Ischemic Heart Disease

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetramericion channels, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase in the expression of different TRPC isoforms was observed in different animal models of heart infarcts and in vitro experimental models of ischemia and reperfusion. TRPC channel-mediated increase of the intracellular Ca2+ concentration seems to be required for the activation of the signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion and to heart infarction

TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling

Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart’s structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.Spanish Ministry of Economy and Competitiveness BFU2016–74932-C2Institute of Carlos III PI15/00203; PI16/00259; CB16/11/00431Andalusia Government PI-0313-201

TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling

Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart’s structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Remodelado de la entrada de calcio en la angiogénesis: papel de las proteínas ORAI1 Y SARAF

La angiogénesis se define como el proceso llevado a cabo por las células endoteliales (CE) por el cual se forman nuevos vasos sanguíneos a partir de otros preexistentes. Su regulación es precisa y está controlada por factores pro-angiogénicos, como el factor de crecimiento vascular endotelial (VEGF). VEGF activa diferentes rutas de señalización que promueven el incremento de las concentraciones de calcio intracelular ([Ca2+]i). Estudios recientes sugieren que el cambio de [Ca2+]i regulado por SOCE, del inglés store-operated calcium entry, tiene un papel fundamental en el proceso de angiogénesis. Sin embargo, siguen siendo escasos los conocimientos sobre el papel que desempeñan en este proceso sus proteínas claves, entre ellas, SARAF, el emergente factor regulador de SOCE, y Orai1, la subunidad formadora del poro de los canales de SOCE. En este estudio demostramos que la inhibición de SOCE usando GSK-7975A (GSK), bloquea el crecimiento de los brotes a partir de anillos de aorta de rata cultivados ex vivo, la migración y la formación de tubos de CE humanas derivadas de la vena umbilical (HUVEC); y afecta significativamente al desarrollo de los vasos de la retina de ratón neonato. Encontramos que Orai1 y SARAF colocalizan en HUVEC y están implicados en el incremento de la [Ca2+]i mediada por VEGF. En esta misma línea, encontramos que la supresión de la expresión de ambas proteínas, usando siARNs, reduce significativamente la formación de tubos, la proliferación y la migración de las HUVEC. Por otra parte, motivados por estudiar la angiogénesis desde un punto de vista traslacional, demostramos que el suero de pacientes que han padecido un infarto severo del corazón con con elevación del segmento ST (STEMI) contiene elevados niveles de VEGF-A e interleuquina 17 A (IL-17A). Además, demostramos que el suero isquémico promueve la formación de tubos y la migración de las HUVEC, así como la atracción de las células tip en cultivo 3D de HUVEC. Igualmente, usando tapsigargina como estímulo de vaciado de reservorios, observamos una exacerbación de SOCE en células tratadas con suero isquémico que se correlacionó con un aumento en la expresión proteica de Orai1. Finalmente, en presencia de suero isquémico, evidenciamos que la inhibición de Orai1 previene la activación de MEF-2A, la migración de las células tip y la expresión de Notch1, Hes1, Hey1 y VEGF-A en HUVEC. Estos hallazgos se corroboraron utilizando suero de ratas sometidas a isquemia/reperfusión (I/R). Nuestros resultados muestran por primera vez la interacción funcional entre SARAF y Orai1 en las CE, remarcan el rol de las proteínas en el proceso de angiogénesis, y relacionan a Orai1 y SOCE con el proceso de angiogénesis post-isquémica.Angiogenesis is the process which is controlled by endothelial cells (EC) to form new blood vessels from preexisting vascular beds. This process is tightly regulated by pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which promote signaling pathways involving an increase in the intracellular Ca2+ concentration ([Ca2+]i). Recent studies suggest that store-operated calcium entry (SOCE) might play a role in angiogenesis. However, little is known regarding the role of SOCE proteins, such as SARAF, the SOCE-associated regulatory factor, and Orai1, the pore-forming subunit of the store-operated calcium channel (SOCC), in this process. In the present study, we demonstrate that SOCE inhibition using GSK-7975A (GSK) blocks ex vivo rat aorta sprouting, as well as human umbilical vein endothelial cells (HUVEC) tube formation and migration. Likewise, the intraperitoneal injection of GSK drastically affects the development of mice retinal vasculature. Moreover, we find that Orai1 and SARAF colocalize in HUVEC and both are involved in VEGF-mediated [Ca2+]i. We also show that Orai1 and SARAF knockdown, using siRNA, impairs HUVEC tube formation, proliferation, and migration. Furthermore, in order to study angiogenesis from a translational perspective, we demonstrated that serum from patients with ST segment elevation myocardial infarction (STEMI) show high levels of VEGF and interleukin 17A (IL-17A). In the same vein, we find that ischemic serum promotes HUVEC tube formation and migration, as well as, tip cells attraction in 3D cell culture of HUVEC. Using thapsigargin to stimulate endoplasmic reticulum (RE) emptying, we observed an exacerbation of SOCE in HUVEC treated with ischemic serum which correlated with Orai1 overexpression. Finally, adding ischemic serum, we demonstrate that Orai1 knockdown prevents MEF-2A activation, tip cells migration and the expression of Notch1, Hes1, Hey1 and VEGF-A in HUVEC. These findings were confirmed using serum from rats after heart ischemia/reperfusion (I/R). Our data show for the first time a functional interaction between SARAF and Orai1 in EC and highlight their essential role in different processes of angiogenesis. In addition, we provided first evidence Orai1 function in angiogenesis induced by myocardial infarction

Emergent role of SARAF and store-operated Ca2+ entry in angiogenesis: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

Meeting Abstract: E–C Coupling Meeting 2021| November 12 2021.Angiogenesis is a multistep process that controls endothelial cell (EC) functioning to form new blood vessels from preexisting vascular beds. This process is tightly regulated by pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which promotes signaling pathways involving the increase in the intracellular Ca2+ concentration ([Ca2+]i). Recent evidence suggests that store-operated Ca2+ entry (SOCE) might play a role in angiogenesis. However, little is known regarding the role of SARAF, SOCE-associated regulatory factor in this process. The aim of this study is to examine the role of SARAF in angiogenesis. In vitro angiogenesis was studied using human umbilical endothelial cells (HUVECs) for tube formation assay and vessel sprouting using rat aortic ring by Matrigel assay supplemented with endothelial cell basal medium enriched with different growth factors (VEGF, FGF, b-EGF, and IGF). HUVECs migration was evaluated by wound healing assay, and HUVECs proliferation using Ki67+ marker. Ex vivo angiogenesis was examined by whole mount mice retina on P6 in neonatal mice injected with increasing concentrations of a SOCE inhibitor, GSK-7975A, on P3, P4, and P5. We observed that SOCE inhibition with GSK-7975A blocks aorta sprouting, as well as HUVEC tube formation and migration. The intraperitoneal injection of GSK-7975A also delays the development of retinal vasculature assessed at postnatal day 6 in mice since it reduces vessel length and the number of junctions while it increases lacunarity. Moreover, we found that knockdown of SARAF using siRNA impairs VEGF-mediated [Ca2+]i increase and HUVEC tube formation, proliferation, and migration. Our data show for the first that SOCE inhibition prevents angiogenesis using different approaches and we provide evidence indicating that SARAF plays a critical role in angiogenesis

Non-coding RNAs and ischemic cardiovascular diseases

The Ischemic Heart Disease (IHD) is considered a clinical condition characterized by myocardial ischemia causing an imbalance between myocardial blood supply and demand, leading to morbidity and mortality across the worldwide. Prompt diagnostic and prognostic represents key factors for the treatment and reduction of the mortality rate. Therefore, one of the newest frontiers in cardiovascular research is related to non-coding RNAs (ncRNAs), which prompted a huge interest in exploring ncRNAs candidates for utilization as potential therapeutic targets for diagnostic and prognostic and/or biomarkers in IHD. However, there are undoubtedly many more functional ncRNAs yet to be discovered and characterized. Here we will discuss our current knowledge and we will provide insight on the roles and effects elicited by some ncRNAs related to IHD.This work was supported by Spanish Ministry of Economy and Competitiveness [BFU2016–74932-C2]; Institute of Carlos III [PI15/00203; PI16/00259; CB16/11/00431]; the Andalusia Government [PI-0313-2016]. This study was co-financed by FEDER Funds.Peer reviewe

TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview of the current knowledge on the implication of TRPC and TRPV in the physiological and pathological processes of some frequent vascular diseases

Corrigendum: SARAF and Orai1 Contribute to Endothelial Cell Activation and Angiogenesis.

[This corrects the article DOI: 10.3389/fcell.2021.639952.]