Antonio Rodríguez‐Sinovas

Instituto de Salud Carlos III

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Marisol Ruíz-Meana

Vall d'Hebron Institut de Recerca

David García‐Dorado

Universitat Autònoma de Barcelona

David García‐Dorado

Instituto de Salud Carlos III

Ignasi Barba

Vall d'Hebron Hospital Universitari

Javier Inserte

Centro de Investigación en Red en Enfermedades Cardiovasculares

Elisabet Miró‐Casas

Universitat Autònoma de Barcelona

Laura Valls-Lacalle

Centro de Investigación en Red en Enfermedades Cardiovasculares

Begoña Benito

Universitat Autònoma de Barcelona

Alberto Cabestrero

Hospital de Sant Joan Despí Moisès Broggi

Cristina Rodrı́guez

Universidad Maimónides

Cooperative Institutions

Centro de Investigación en Red en Enfermedades Cardiovasculares

119

Universitat Autònoma de Barcelona

114

Centro de Investigación Biomédica en Red

110

Instituto de Salud Carlos III

103

Vall d'Hebron Hospital Universitari

Vall d'Hebron Institut de Recerca

Consejo Superior de Investigaciones Científicas

Universitat de Barcelona

Charité - Universitätsmedizin Berlin

Inserm

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Rhythmic oscillating complexes in gastrointestinal tract of chickens: a role for motilin

AJP Gastrointestinal and Liver Physiology (1997)

Antonio Rodríguez‐Sinovas Marcel Jiménez P. De Clercq T Peeters Patri Vergara

Rhythmic oscillating complex (ROC) is a highly organized gastrointestinal motility pattern recently described in fasted avian species. ROCs show several high-speed aborad-propagated contractions that progressively change into others of orad direction. In addition, chickens show migrating motor complexes (MMC) in both fed and fasting states. Recently, motilin was isolated and characterized from chicken small intestine. Accordingly, the aim of this study was to learn whether chicken motilin might be involved in either ROC or MMC induction. Electromyographic recordings were obtained from different areas of the gastrointestinal tract of chickens while motilin was infused. The response to chicken motilin was dose dependent in both fed and fasted animals; a bolus of 4 x 10(-11) mol/kg (n = 5) did not modify the intestinal motor pattern, whereas 4 x 10(-10) and 4 x 10(-9) mol/kg (n = 5 each) induced a complete ROC pattern of 5.2 +/- 0.6 and 10.8 +/- 0.9 min, respectively. ROCs induced by chicken motilin presented exactly the same pattern as that described during a spontaneous ROC. Furthermore, motilin concentration in plasma, measured by radioimmunoassay, increased during a spontaneous ROC. This study suggests that chicken motilin triggers an ROC in chickens. The fact that plasma motilin levels increased during spontaneous ROC strongly suggests that motilin is involved in the induction of the ROC pattern. Motilin seems to play a different role in avian and mammalian species, because a phase III of the MMC was never induced by motilin infusion.

Motilin

Migrating motor complex

Gastrointestinal hormone

10.1152/ajpgi.1997.272.4.g916

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Citations (16)

Aging Impairs Reverse Remodeling and Recovery of Ventricular Function after Isoproterenol-Induced Cardiomyopathy

International Journal of Molecular Sciences (2021)

Laia Yáñez-Bisbe Anna García-Elías Marta Tajes Isaac Almendros Antonio Rodríguez‐Sinovas

Information about heart failure with reduced ejection fraction (HFrEF) in women and the potential effects of aging in the female heart is scarce. We investigated the vulnerability to develop HFrEF in female elderly mice compared to young animals, as well as potential differences in reverse remodeling. First, HF was induced by isoproterenol infusion (30 mg/kg/day, 28 days) in young (10-week-old) and elderly (22-month-old) female mice. In a second set of animals, mice underwent isoproterenol infusion followed by no treatment during 28 additional days. Cardiac remodeling was assessed by echocardiography, histology and gene expression of collagen-I and collagen-III. Following isoproterenol infusion, elderly mice developed similar HFrEF features compared to young animals, except for greater cell hypertrophy and tissue fibrosis. After beta-adrenergic withdrawal, young female mice experienced complete reversal of the HFrEF phenotype. Conversely, reversed remodeling was impaired in elderly animals, with no significant recovery of LV ejection fraction, cardiomyocyte hypertrophy and collagen deposition. In conclusion, chronic isoproterenol infusion is a valid HF model for elderly and young female mice and induces a similar HF phenotype in both. Elderly animals, unlike young, show impaired reverse remodeling, with persistent tissue fibrosis and cardiac dysfunction even after beta-adrenergic withdrawal.

Ventricular remodeling

Myocardial fibrosis

10.3390/ijms23010174

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Citations (9)

1319 Onset of cell-to-cell electrical uncoupling precedes rigor contracture and conduction blockade in isolated rat hearts

European Heart Journal (2003)

Antonio Rodríguez‐Sinovas

10.1016/s0195-668x(03)94577-5

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Reperfusion injury as a therapeutic challenge in patients with acute myocardial infarction

Heart Failure Reviews (2007)

Antonio Rodríguez‐Sinovas Yaser Abdallah Hans Michael Piper David García‐Dorado

10.1007/s10741-007-9039-9

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Calcium-mediated cell death during myocardial reperfusion

Cardiovascular Research (2012)

David García‐Dorado Marisol Ruíz-Meana J INSERTE Antonio Rodríguez‐Sinovas H. M. Piper

Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca(2+) handling was initially considered an essential mechanism of reperfusion-induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca(2+)-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca(2+)-dependent cell death in light of these new observations. Altered Ca(2+) handling includes increased cytosolic Ca(2+) levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca(2+) transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca(2+) microdomains. In the opposite direction, permeability transition can worsen altered Ca(2+) handling and favour hypercontracture. Ca(2+) appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca(2+)-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca(2+) influx, intracellular Ca(2+) handling, or Ca(2+)-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact.

Calcium in biology

Reperfusion Therapy

10.1093/cvr/cvs116

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Citations (275)

Angiotensin II-induced cardiomyocyte hypertrophy: A complex response dependent on intertwined pathways

Revista Portuguesa de Cardiologia (2021)

Marta Consegal Laura Valls-Lacalle Antonio Rodríguez‐Sinovas

10.1016/j.repc.2020.12.009

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Combination therapy with remote ischaemic conditioning and insulin or exenatide enhances infarct size limitation in pigs

Cardiovascular Research (2015)

Juan J. Alburquerque-Béjar Ignasi Barba Javier Inserte Elisabet Miró‐Casas Marisol Ruíz-Meana

Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in patients. Our objective was to investigate whether the combination of RIC with either exenatide or glucose–insulin–potassium (GIK) is more effective than RIC alone. Pigs were submitted to 40 min of coronary occlusion followed by reperfusion, and received (i) no treatment, (ii) one of the following treatments: RIC (5 min ischemia/5 min reperfusion × 4), GIK, or exenatide (at doses reducing infarct size in clinical trials), or (iii) a combination of two of these treatments (RIC + GIK or RIC + exenatide). After 5 min of reperfusion (n = 4/group), prominent phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) was observed, both in control and reperfused myocardium, in animals receiving GIK, and mitochondria from these hearts showed reduced ADP-stimulated respiration. 1H NMR-based metabonomics disclosed a shift towards increased glycolysis in GIK and exenatide groups. In contrast, oxidative stress (myocardial nitrotyrosine levels) and eNOS uncoupling were significantly reduced only by RIC. In additional experiments (n = 7–10/group), ANOVA demonstrated a significant effect of the number of treatments after 2 h of reperfusion on infarct size (triphenyltetrazolium, % of the area at risk; 59.21 ± 3.34, 36.64 ± 3.03, and 21.04 ± 2.38% for none, one, and two treatments, respectively), and significant differences between one and two treatments (P = 0.004) but not among individual treatments or between RIC + GIK and RIC + exenatide. GIK and exenatide activate cardioprotective pathways different from those of RIC, and have additive effects with RIC on infarct size reduction in pigs.

Nitrotyrosine

10.1093/cvr/cvv171

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Citations (54)

Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection

The Journal of Physiology (2010)

Antonio Rodríguez‐Sinovas José A. Sánchez‐Alcázar Alejandra González‐Loyola Ignasi Barba Miriam Morente

Connexin 43 (Cx43) plays an important role in cardioprotective signalling by mechanisms at least in part independent of gap junctional communication. To investigate whether this role is related to specific properties of this connexin isoform, we used a knock-in mouse model in which the coding region of Cx43 is replaced by that of Cx32. Homozygous Cx43KI32 mice showed reduced cell-to-cell Lucifer Yellow transfer (P < 0.01), but QRS duration and left ventricular fractional shortening (echocardiography) were similar to those in wild-type animals. NMR spectroscopy detected reduced ATP and increased lactate content in myocardium from homozygous Cx43KI32 animals (P < 0.05). Despite this, isolated homozygous Cx43KI32 hearts showed smaller infarcts after ischaemia-reperfusion (40 min/60 min) as compared to hearts from heterozygous and wild-type animals (13 and 31% reduction, respectively, P < 0.05). Cardiac myocytes isolated from Cx43KI32 mouse hearts also showed a reduced rate of cell death after simulated ischaemia-reperfusion. In a separate series of experiments, both ischaemic (4 cycles of 3.5 min of ischaemia and 5 min of reperfusion) and pharmacological (50 micromol l(-1) diazoxide, 10 min) preconditioning reduced infarct size in hearts from wild-type mice (by 24.84 and 26.63%, respectively, P < 0.05), but only ischaemic preconditioning was effective in hearts from heterozygous animals and both preconditioning strategies failed to protect Cx43KI32 homozygous hearts. These results demonstrate that Cx43 has an important and previously unknown modulatory effect in myocardial energy metabolism and tolerance to ischaemia, and plays a critical role in preconditioning protection, by mechanisms that are specific for this connexin isoform.

Substitution (logic)

Myocardial ischaemia

10.1113/jphysiol.2009.186577

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Citations (49)

Cx43 phosphorylation and cardioprotection

Cardiovascular Research (2009)

Antonio Rodríguez‐Sinovas

Connexin-43 (Cx43), a transmembrane protein able to oligomerize into hexamers around a central pore, is the main protein-forming gap junctional channels in ventricular cardiomyocytes. Altered Cx43 expression or distribution has been shown to impair propagation of electrical impulses and promote arrhythmias during ischaemia and reperfusion.1 However, in the past few years, it has become evident that the role of Cx43 in myocardial ischaemia pathophysiology goes beyond its role in arrhythmogenesis. Gap junction uncouplers have been shown to limit infarct size after ischaemia in different tissues, including heart2 and brain,3 thus supporting a role for gap junctions in intercellular spreading of injury during ischaemia–reperfusion. These findings were further strengthened by studies in heterozygous Cx43-deficient mice (Cx43+/−) submitted to chronic ischaemia without reperfusion,4 which showed reduced infarctions in mutant animals. However, the involvement of Cx43 in the pathophysiology of ischaemia–reperfusion injury is not restricted to the spreading of injury, and several studies suggest an important role in cardioprotection.5,6 In this context, the study by Srisakuldee et al. 7 adds important information on the cardioprotective role of Cx43. The authors demonstrate that both ischaemic preconditioning and pretreatment with diazoxide are able to induce, in isolated rat hearts, specific phosphorylation of … *Corresponding author. Tel: +34 93 489 4134; fax: +34 934894032. E-mail address : arodriguez{at}ir.vhebron.net

Cardioprotection

Pathophysiology

10.1093/cvr/cvp227

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Citations (7)

Inhibition of ATP-citrate lyase by bempedoic acid protects against abdominal aortic aneurysm formation in mice

Biomedicine & Pharmacotherapy (2025)

Lídia Puertas-Umbert Judith Alonso Laia Blanco-Casoliva Rafael Almendra‐Pegueros Mercedes Camacho

ATP citrate lyase

Lyase

10.1016/j.biopha.2025.117876

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