Novel Strategies to Improve the Cardioprotective Effects of Cardioplegia.

The use of cardioprotective strategies as adjuvants of cardioplegic solutions has become an ideal alternative for the improvement of post-surgery heart recovery. The choice of the optimal cardioplegia, as well as its distribution mechanism, remains controversial in the field of cardiovascular surgery. There is still a need to search for new and better cardioprotective methods during cardioplegic procedures. New techniques for the management of cardiovascular complications during cardioplegia have evolved with new alternatives and additives, and each new strategy provides a tool to neutralize the damage after ischemia/reperfusion events. Researchers and clinicians have committed themselves to studying the effect of new strategies and adjuvant components with the potential to improve the cardioprotective effect of cardioplegic solutions in preventing myocardial ischemia/reperfusion-induced injury during cardiac surgery. The aim of this review is to explore the different types of cardioplegia, their protection mechanisms, and which strategies have been proposed to enhance the function of these solutions in hearts exposed to cardiovascular pathologies that require surgical alternatives for their corrective progression.

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas / Cardiotrophin-1 and Insulin like growth factor induced by exercise are associated to cardiac hypertrophy in marathon runners

Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.

Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.

Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1.

Introduction: Cardiovascular diseases, especially metabolic-related disorders, are progressively growing worldwide due to high-fat-containing foods, which promote a deleterious response at the cellular level, termed lipotoxicity, or lipotoxic stress. At the cardiac level, saturated fatty acids have been directly associated with cardiomyocyte lipotoxicity through various pathological mechanisms involving mitochondrial dysfunction, oxidative stress, and ceramide production, among others. However, integrative regulators connecting saturated fatty acid-derived lipotoxic stress to mitochondrial and cardiomyocyte dysfunction remain elusive. Methods: Here, we worked with a cardiomyocyte lipotoxicity model, which uses the saturated fatty acid myristate, which promotes cardiomyocyte hypertrophy and insulin desensitization. Results: Using this model, we detected an increase in the mitochondrial E3 ubiquitin ligase, MUL1, a mitochondrial protein involved in the regulation of growth factor signaling, cell death, and, notably, mitochondrial dynamics. In this context, myristate increased MUL1 levels and induced mitochondrial fragmentation, associated with the decrease of the mitochondrial fusion protein MFN2, and with the increase of the mitochondrial fission protein DRP1, two targets of MUL1. Silencing of MUL1 prevented myristate-induced mitochondrial fragmentation and cardiomyocyte hypertrophy. Discussion: These data establish a novel connection between cardiomyocytes and lipotoxic stress, characterized by hypertrophy and fragmentation of the mitochondrial network, and an increase of the mitochondrial E3 ubiquitin ligase MUL1.

Targeting VCAM-1: a therapeutic opportunity for vascular damage.

INTRODUCTION: The vascular cell adhesion molecule (VCAM-1) is a transmembrane sialoglycoprotein detected in activated endothelial and vascular smooth muscle cells involved in the adhesion and transmigration of inflammatory cells into damaged tissue. Widely used as a pro-inflammatory marker, its potential role as a targeting molecule has not been thoroughly explored. AREAS COVERED: We discuss the current evidence supporting the potential targeting of VCAM-1 in atherosclerosis, diabetes, hypertension and ischemia/reperfusion injury. EXPERT OPINION: There is emerging evidence that VCAM-1 is more than a biomarker and may be a promising therapeutic target for vascular diseases. While there are neutralizing antibodies that allow preclinical research, the development of pharmacological tools to activate or inhibit this protein are required to thoroughly assess its therapeutic potential.

Effects of Trimetazidine on Right Ventricular Function and Ventricular Remodeling in Patients with Pulmonary Artery Hypertension: A Randomised Controlled Trial.

BACKGROUND: Pulmonary artery hypertension (PAH) is a chronic and progressive disease. Although current therapy has improved the disease prognosis, PAH has a poor survival rate. The key feature leading to disease progression and death is right ventricular (RV) failure. METHODS AND RESULTS: We assessed the role of trimetazidine, a fatty acid beta-oxidation (FAO) inhibitor, in right ventricular function, remodeling, and functional class in PAH patients, with a placebo-controlled double-blind, case-crossover trial. Twenty-seven PAH subjects were enrolled, randomized, and assigned to trimetazidine or placebo for three months and then reallocated to the other study arm. The primary endpoint was RV morphology and function change after three months of treatment. Secondary endpoints were the change in exercise capacity assessed by a 6 min walk test after three months of treatment and the change in pro-BNP and Galectin-3 plasma levels after three months. Trimetazidine use was safe and well-tolerated. After three months of treatment, patients in the trimetazidine group showed a small but significant reduction of RV diastolic area, and a substantial increase in the 6 min walk distance (418 vs. 438 mt, p = 0.023), without significant changes in biomarkers. CONCLUSIONS: A short course of trimetazidine is safe and well-tolerated on PAH patients, and it is associated with significant increases in the 6MWT and minor but significant improvement in RV remodeling. The therapeutic potential of this drug should be evaluated in larger clinical trials.

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes.

A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca2+) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca2+-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca2+ uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca2+ transport. In conclusion, IGF-1-induced mitochondrial Ca2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.

A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is one of the most complex and most prevalent cardiometabolic diseases in aging population. Age, obesity, diabetes, and hypertension are the main comorbidities of HFpEF. Microvascular dysfunction and vascular remodeling play a major role in its development. Among the many mechanisms involved in this process, vascular stiffening has been described as one the most prevalent during HFpEF, leading to ventricular-vascular uncoupling and mismatches in aged HFpEF patients. Aged blood vessels display an increased number of senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). This is consistent with the fact that EC and cardiomyocyte cell senescence has been reported during HFpEF. Autophagy plays a major role in VSMCs physiology, regulating phenotypic switch between contractile and synthetic phenotypes. It has also been described that autophagy can regulate arterial stiffening and EC and VSMC senescence. Many studies now support the notion that targeting autophagy would help with the treatment of many cardiovascular and metabolic diseases. In this review, we discuss the mechanisms involved in autophagy-mediated vascular senescence and whether this could be a driver in the development and progression of HFpEF.

Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Epidemiological studies indicate that pre-menopausal women are more protected against the development of CVDs compared to men of the same age. This effect is attributed to the action/effects of sex steroid hormones on the cardiovascular system. In this context, estrogen modulates cardiovascular function in physiological and pathological conditions, being one of the main physiological cardioprotective agents. Here we describe the common pathways and mechanisms by which estrogens modulate the retrograde and anterograde communication between the nucleus and mitochondria, highlighting the role of genomic and non-genomic pathways mediated by estrogen receptors. Additionally, we discuss the presumable role of bromodomain-containing protein 4 (BRD4) in enhancing mitochondrial biogenesis and function in different CVD models and how this protein could act as a master regulator of estrogen protective activity. Altogether, this review focuses on estrogenic control in gene expression and molecular pathways, how this activity governs nucleus-mitochondria communication, and its projection for a future generation of strategies in CVDs treatment.

Angiotensin-(1-9) in hypertension.

Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting enzyme type 2 (ACE2). Using osmotic minipumps, infusion of Ang-(1-9) consistently reduces blood pressure in several rat hypertension models. In these animals, hypertension-induced end-organ damage is also decreased. Several pieces of evidence suggest that Ang-(1-9) is the endogenous ligand that binds and activates the type-2 angiotensin II receptor (AT2R). Activation of AT2R triggers different tissue-specific signaling pathways. This phenomenon could be explained by the ability of AT2R to form different heterodimers with other G protein-coupled receptors. Because of the antihypertensive and protective effects of AT2R activation by Ang-(1-9), associated with a short half-life of RAS peptides, several synthetic AT2R agonists have been synthesized and assayed. Some of them, particularly CGP42112, C21 and novokinin, have demonstrated antihypertensive properties. Only two synthetic AT2R agonists, C21 and LP2-3, have been tested in clinical trials, but none of them like an antihypertensive. Therefore, Ang-(1-9) is a promising antihypertensive drug that reduces hypertension-induced end-organ damage. However, further research is required to translate this finding successfully to the clinic.

Mitochondrial E3 ubiquitin ligase 1 (MUL1) as a novel therapeutic target for diseases associated with mitochondrial dysfunction.

Mitochondrial E3 ubiquitin ligase 1 (MUL1) is a mitochondrial outer membrane-anchored protein-containing transmembrane domain in its N- and C-terminal regions, where both are exposed to the cytosol. Interestingly the C-terminal region has a RING finger domain responsible for its E3 ligase activity, as ubiquitin or in SUMOylation, interacting with proteins related to mitochondrial fusion and fission, cell survival, and tumor suppressor process, such as Akt. Therefore, MUL1 is involved in various cellular processes, such as mitochondrial dynamics, inter-organelle communication, proliferation, mitophagy, immune response, inflammation and cell apoptosis. MUL1 is expressed at a higher basal level in the heart, immune system organs, and blood. Here, we discuss the role of MUL1 in mitochondrial dynamics and its function in various pathological models, both in vitro and in vivo. In this context, we describe the role of MUL1 in: (1) the inflammatory response, by regulating NF-κB activity; (2) cancer, by promoting cell death and regulating exonuclear function of proteins, such as p53; (3) neurological diseases, by maintaining communication with other organelles and interacting with proteins to eliminate damaged organelles and; (4) cardiovascular diseases, by maintaining mitochondrial fusion/fission homeostasis. In this review, we summarize the latest advances in the physiological and pathological functions of MUL1. We also describe the different substrates of MUL1, acting as a positive or negative regulator in various pathologies associated with mitochondrial dysfunction. In conclusion, MUL1 could be a potential key target for the development of therapies that focus on ensuring the functionality of the mitochondrial network and, furthermore, the quality control of intracellular components by synchronously modulating the activity of different cellular mechanisms involved in the aforementioned pathologies. This, in turn, will guide the development of targeted therapies.

Regulation of total LC3 levels by angiotensin II in vascular smooth muscle cells.

Hypertension is associated with high circulating angiotensin II (Ang II). We have reported that autophagy regulates Ang II-induced vascular smooth muscle cell (VSMC) hypertrophy, but the mechanism mediating this effect is still unknown. Therefore, we studied how Ang II regulates LC3 levels in VSMCs and whether Bag3, a co-chaperone known to regulate LC3 total levels, may be involved in the effects elicited by Ang II. A7r5 cell line or rat aortic smooth muscle cell (RASMC) primary culture were stimulated with Ang II 100 nM for 24 h and LC3 I, LC3 II and Bag3 protein levels were determined by Western blot. MAP1LC3B mRNA levels were assessed by RT-qPCR. Ang II increased MAP1LC3B mRNA levels and protein levels of LC3 I, LC3 II and total LC3 (LC3 I + LC3 II). Cycloheximide, but not actinomycin D, abolished LC3 II and total LC3 increase elicited by Ang II in RASMCs. In A7r5 cells, cycloheximide prevented the Ang II-mediated increase of LC3 I and total LC3, but not LC3 II. Moreover, Ang II increased Bag3 levels, but this increase was not observed upon co-administration with either losartan 1 µM (AT1R antagonist) or Y-27632 10 µM (ROCK inhibitor). These results suggest that Ang II may regulate total LC3 content through transcriptional and translational mechanisms. Moreover, Bag3 is increased in response to Ang II by a AT1R/ROCK signalling pathway. These data provide preliminary evidence suggesting that Ang II may stimulate autophagy in VSMCs by increasing total LC3 content and LC3 processing.

Circulating Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Associated With Left Atrial Remodeling in Long-Distance Runners.

Introduction: An increased risk of atrial fibrillation (AF) has been demonstrated in high-performance athletes. Soluble vascular adhesion molecule-1 (sVCAM-1), a biomarker involved in inflammation and cardiac remodeling, is associated with the development of AF in the general population. However, the relationship between sVCAM-1 and left atrial (LA) remodeling has been poorly investigated in long-distance runners (LDR). Aim: To determine the association between LA remodeling and sVCAM-1 levels in LDR during the training period before a marathon race. Methods: Thirty-six healthy male LDR (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V°O2-peak: 56.5 ± 7.3 mL·kg-1·min-1) were evaluated in this single-blind and cross-sectional study. The LDR were separated into two groups according to previous training levels: high-training (HT) (n = 18) ≥100 km·week-1 and low-training (LT) (n = 18) ≥70 and <100 km·week-1. Also, 18 healthy non-active subjects were included as a control group (CTR). In all participants, transthoracic echocardiography was performed. sVCAM-1 blood levels were measured baseline and immediately finished the marathon race in LDR. Results: HT showed increased basal levels of sVCAM-1 (651 ± 350 vs. 440 ± 98 ng·mL-1 CTR, p = 0.002; and vs. 533 ± 133 ng·mL-1 LT; p = 0.003) and a post-marathon increase (ΔsVCAM-1) (651 ± 350 to 905 ± 373 ng·mL-1; p = 0.002), that did not occur in LT (533 ± 133 to 651 ± 138 ng·mL-1; p = 0.117). In LDR was a moderate correlation between LA volume and sVCAM-1 level (rho = 0.510; p = 0.001). Conclusions: In male long-distance runners, sVCAM-1 levels are directly associated with LA remodeling. Also, the training level is associated with basal sVCAM-1 levels and changes after an intense and prolonged exercise (42.2 km). Whether sVCAM-1 levels predict the risk of AF in runners remains to be established.

Left Cardiac Remodelling Assessed by Echocardiography Is Associated with Rho-Kinase Activation in Long-Distance Runners.

This single-blind and cross-sectional study evaluated the role of Rho-kinase (ROCK) as a biomarker of the cardiovascular remodelling process assessed by echocardiography in competitive long-distance runners (LDRs) during the training period before a marathon race. Thirty-six healthy male LDRs (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V˙ O2-peak: 56.5 ± 7.3 mL·kg-1·min-1) were separated into two groups according to previous training level: high-training (HT, n = 16) ≥ 100 km·week-1 and low-training (LT, n = 20) ≥ 70 and < 100 km·week-1. Also, twenty-one healthy nonactive subjects were included as a control group (CTR). A transthoracic echocardiography was performed and ROCK activity levels in circulating leukocytes were measured at rest (48 h without exercising) the week before the race. The HT group showed a higher left ventricular mass index (LVMi) and left atrial volume index (LAVi) than other groups (p < 0.05, for both); also, higher levels of ROCK activity were found in LDRs (HT = 6.17 ± 1.41 vs. CTR = 1.64 ± 0.66 (p < 0.01); vs. LT = 2.74 ± 0.84; (p < 0.05)). In LDRs a direct correlation between ROCK activity levels and LVMi (r = 0.83; p < 0.001), and LAVi (r = 0.70; p < 0.001) were found. In conclusion, in male competitive long-distance runners, the load of exercise implicated in marathon training is associated with ROCK activity levels and the left cardiac remodelling process assessed by echocardiography.

Soluble Interleukin-6 Receptor Regulates Interleukin-6-Dependent Vascular Remodeling in Long-Distance Runners.

Little is known about the effects of training load on exercise-induced plasma increase of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) and their relationship with vascular remodeling. We sought to evaluate the role of sIL 6R as a regulator of IL-6-induced vascular remodeling. Forty-four male marathon runners were recruited and allocated into two groups: low-training (LT, <100 km/week) and high-training (HT, ≥100 km/week), 22 athletes per group. Twenty-one sedentary participants were used as reference. IL-6, sIL-6R and sgp130 levels were measured in plasma samples obtained before and immediately after finishing a marathon (42.2-km). Aortic diameter was measured by echocardiography. The inhibitory effect of sIL-6R on IL-6-induced VSMC migration was assessed using cultured A7r5 VSMCs. Basal plasma IL-6 and sIL-6R levels were similar among sedentary and athlete groups. Plasma IL-6 and sIL-6R levels were elevated after the marathon, and HT athletes had higher post-race plasma sIL-6R, but not IL-6, level than LT athletes. No changes in sgp130 plasma levels were found in LT and HT groups before and after running the marathon. Athletes had a more dilated ascending aorta and aortic root than sedentary participants with no differences between HT and LT athletes. However, a positive correlation between ascending aorta diameter and plasma IL-6 levels corrected by training load and years of training was observed. IL-6 could be responsible for aorta dilation because IL-6 stimulated VSMC migration in vitro, an effect that is inhibited by sIL-6R. However, IL-6 did not modify cell proliferation, collagen type I and contractile protein of VSMC. Our results suggest that exercise induces vascular remodeling. A possible association with IL-6 is proposed. Because sIL-6R inhibits IL-6-induced VSMC migration, a possible mechanism to regulate IL-6-dependent VSMC migration is also proposed.

Polycystin-1 is required for insulin-like growth factor 1-induced cardiomyocyte hypertrophy.

Cardiac hypertrophy is the result of responses to various physiological or pathological stimuli. Recently, we showed that polycystin-1 participates in cardiomyocyte hypertrophy elicited by pressure overload and mechanical stress. Interestingly, polycystin-1 knockdown does not affect phenylephrine-induced cardiomyocyte hypertrophy, suggesting that the effects of polycystin-1 are stimulus-dependent. In this study, we aimed to identify the role of polycystin-1 in insulin-like growth factor-1 (IGF-1) signaling in cardiomyocytes. Polycystin-1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. We then investigated the molecular mechanism underlying this result. We found that polycystin-1 silencing impaired the activation of the IGF-1 receptor, Akt, and ERK1/2 elicited by IGF-1. Remarkably, IGF-1-induced IGF-1 receptor, Akt, and ERK1/2 phosphorylations were restored when protein tyrosine phosphatase 1B was inhibited, suggesting that polycystin-1 knockdown deregulates this phosphatase in cardiomyocytes. Moreover, protein tyrosine phosphatase 1B inhibition also restored IGF-1-dependent cardiomyocyte hypertrophy in polycystin-1-deficient cells. Our findings provide the first evidence that polycystin-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.

Polycystin-1 regulates cardiomyocyte mitophagy.

Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The analysis of mitochondrial morphology from cardiomyocytes of heterozygous PC1 mice (PDK1+/- ) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria density and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphology. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphology, and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphology and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.

VCAM-1 as a predictor biomarker in cardiovascular disease.

The vascular cellular adhesion molecule-1 (VCAM-1) is a protein that canonically participates in the adhesion and transmigration of leukocytes to the interstitium during inflammation. VCAM-1 expression, together with soluble VCAM-1 (sVCAM-1) induced by the shedding of VCAM-1 by metalloproteinases, have been proposed as biomarkers in immunological diseases, cancer, autoimmune myocarditis, and as predictors of mortality and morbidity in patients with chronic heart failure (HF), endothelial injury in patients with coronary artery disease, and arrhythmias. This revision aims to discuss the role of sVCAM-1 as a biomarker to predict the occurrence, development, and preservation of cardiovascular disease.

Role of Interleukin-6 in Vascular Health and Disease.

IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

Impact of the Potential Antitumor Agent 2-(4-Hydroxyphenyl) Amino-1,4-Naphthoquinone (Q7) on Vasomotion Is Mediated by the Vascular Endothelium, But Not Vascular Smooth Muscle Cell Metabolism.

ABSTRACT: Vasomotion is defined as rhythmic oscillations in arterial diameter that regulate the blood flow and blood pressure. Because antitumor treatment may impair vascular functions and increase the blood pressure, we sought to evaluate whether a new naphthoquinone derivative, postulated as an antitumor agent, manifests adverse effects on vascular function. In this article, we evaluated the toxicity of 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) and its effects on vascular vasomotion in 3 models of vascular structure: endothelial cells, aortic ring, and smooth muscle cells. Although showing nontoxic effects, Q7 inhibited the formation of capillary-like structures of the EA.hy926 endothelial cell line grown on Matrigel. In exvivo experiments with aortic rings precontracted with phenylephrine (PE, 10-6 M), Q7 (10-5 M) significantly (P < 0.05) reduced vascular rhythmic contractions induced by the acetylcholine (ACh; 10-7-10-5 M), whereas sodium nitroprusside (a nitric oxide donor; 10-8 M) recovered the vasomotion. Furthermore, Q7 (10-5 M) did not decrease KCl-induced vascular rhythmic contractions in the aortic rings precontracted with BaCl2 (a nonselective K+ channel blocker; 10-3 M). Vascular smooth muscle cells (A7r5) preincubated with Q7 (10-5 M) for 3 hours also demonstrated a reduced glucose uptake. However, the Adenosine Triphosphate content was unaffected, suggesting that the rapid reduction in vasomotion observed in vascular reactivity experiments did not involve cellular metabolism but may be due to faster mechanisms involving endothelial nitric oxide and K+ channels leading to oscillations in intracellular Ca2+. In summary, the naphthoquinone derivative Q7 presents low cytotoxicity yet may alter the endothelial cell response and vasomotion in the absence of changes in smooth muscle cell metabolism.