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Background: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. Methods: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague–Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. Results: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% ( P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. Conclusions: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.

Resumen: Introducción: Los ratones SR-B1 KO/ApoER6 1h/h que son alimentados con una dieta rica en grasas saturadas, desarrollan enfermedad coronaria aterosclerótica severa, complicaciones isquémicas e insuficiencia cardíaca, con alta mortalidad. Los estudios con este modelo se han enfocado fundamentalmente en la enfermedad coronaria y menos en el remodelado cardíaco. El objetivo del trabajo ha sido caracterizar el remodelado miocárdico, evaluar la evolución temporal de la función ventricular izquierda y la sobrevida asociada a enfermedad cardíaca por ateromatosis. Método: Ratones homocigotos SR-B1 KO/ApoER6 1h/h fueron alimentados por 8 semanas con dieta aterogénica o dieta normal y se comparó la sobrevida en ambos grupos. A las 4 semanas se realizó un ecocardiograma bidimensional. En los ratones eutanasiados se evaluó en la pared cardíaca fibrosis miocárdica y tamaño de los cardiomiocitos por morfometría, apoptosis con técnica de TUNEL e infiltración por células inflamatorias mononucleares (ED1) por inmunohistoquímica. Resultados: En el grupo que recibió dieta aterogénica la sobrevida se redujo en 46,7% (p < 0.001), debido a muerte súbita y a falla cardíaca progresiva. En este grupo, a las 4 semanas se observó dilatación de cavidades izquierdas y disminución de la fracción de eyección del ventrículo izquierdo en comparación con el grupo control (79,3 ± 1,3% vs 66 ± 3,7%, p

In December 2019, a new type of coronavirus emerged in the city of Wuhan, China This novel virus has unleashed a pandemic that has inflicted a considerable impact on public health and the economy and has therefore become a severe concern worldwide This new virus -named SARS-CoV-2has been rapidly investigated in order to create knowledge aimed at achieving its control Comparative studies with SARS-CoV virus, responsible for the 2002-2003 pandemic, suggest that SARS-CoV-2 requires the same receptor to bind and infect cells: angiotensin converting enzyme 2 (ACE-2) This hypothesis has been thoroughly supported by a variety of in vitro research and is currently considered a potential therapeutic target ACE-2 is part of the counter-regulatory renin-angiotensin system, exerting effects in pulmonary, renal and cardiovascular systems In this context, concerns have arisen in regards to the vulnerability of hypertensive patients against COVID-19, given that there is evidence that may suggest that polymorphisms associated to hypertension may increase the expression of ACE-2 Moreover, preclinical studies have shown that antihypertensive drugs may increase the expression of this enzyme In this review article, we present the current state of the art on this polemic topic Our critical analysis suggest that there is no robust clinical evidence supporting the hypothesis that the use of antihypertensive drugs can increase vulnerability to infection with SARS-CoV-2 Therefore, we recommend that the use of these therapeutic agents should not be discontinued in hypertensive patients in risk to or suffering COVID-19

Background: Angiotensin II is a potent activator of the Rho-kinase (ROCK) pathway, through which it exerts some of its adverse vasoconstrictor effects. Clinical evidence on the effects of blocking the angiotensin II receptor 1 on ROCK activity in hypertensive patients is scarce. Objective: To demonstrate that ROCK activity in peripheral blood mononuclear cells (PMBCs) in patients with essential hypertension is reduced earlier than previously observed, along with blood pressure (BP) lowering on treatment with olmesartan. Methods: Prospective pilot open study; 17 hypertensive patients were treated with progressive olmesartan doses starting with 20 mg qd. BP was measured at 3, 6 and 9 weeks after treatment initiation. If treatment failed to normalize BP after 3 weeks, olmesartan dose was increased to 40 mg qd, and if still hypertensive after 6 weeks, 12.5 mg of hydrochlorothiazide qd was added. ROCK activity was measured at baseline and 9 weeks after treatment as myosin phosphatase target subunit 1 phosphorylation (MYPT1-p/T ratio) in PBMC. Results: Mean baseline BP was 162 ± 4.9/101 ± 2.4 mmHg. After 9 weeks of treatment, both systolic and diastolic BP were reduced by 41 and 22 mmHg, respectively (p Conclusion: Normotension achieved after 9 weeks in 82% of the patients treated with olmesartan was associated with a significant reduction of ROCK activity in PBMC.

Background Increased Rho‐kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho‐kinase pathway components an on the relationship between Rho‐kinase and apoptosis. Here, Rho‐kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. Methods Cross‐sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho‐kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin‐radixin‐moesin (ERM) phosphorylation. Rho‐kinase cascade proteins phosphorylation p38‐MAPK, myosin light chain‐2, JAK and JNK were also analysed along with apoptosis. Results MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9‐ and 4.8‐fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38‐MAPK and myosin light chain‐2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin‐(1‐9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8‐fold compared with controls and significantly correlated with Rho‐kinase activation. Conclusion Rho‐kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.

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.

Ang-(1-9) peptide is a bioactive vasodilator peptide that prevents cardiomyocyte hypertrophy in vitro and in vivo as well as lowers blood pressure and pathological cardiovascular remodeling, however, it has a reduced half-life in circulation, requiring a suitable carrier for its delivery. In this work, hybrid nanoparticles composed of polymeric nanoparticles (pNPs) based on Eudragit® E/Alginate (EE/Alg), and gold nanospheres (AuNS), were developed to evaluate their encapsulation capacity and release of Ang-(1-9) under different experimental conditions. Hybrid pNPs were characterized by dynamic light scattering, zeta potential, transmission and scanning electron microscopy, size distribution, and concentration by nanoparticle tracking analysis. Nanometric pNPs, with good polydispersity index and colloidally stable, produced high association efficiency of Ang-(1-9) and controlled release. Finally, the treatment of neonatal cardiomyocytes in culture with EE/Alg/AuNS 2% + Ang-(1-9) 20% pNPs decreased the area and perimeter, demonstrating efficacy in preventing norepinephrine-induced cardiomyocyte hypertrophy. On the other hand, the incorporation of AuNS did not cause negative effects either on the cytotoxicity or on the association capacity of Ang-(1-9), suggesting that the hybrid carrier EE/Alg/AuNS pNPs could be used for the delivery of Ang-(1-9) in the treatment of cardiovascular 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.

Angiotensin-(1-9), a component of the non-canonical renin-angiotensin system, has a short half-life in blood. This peptide has shown to prevent and/or attenuate hypertension and cardiovascular remodeling. A controlled release of angiotensin-(1-9) is needed for its delivery to the heart. Our aim was to develop a drug delivery system for angiotensin-(1-9). Thermosensitive liposomes (LipoTherm) were prepared with gold nanoclusters (LipoTherm-AuNC) to increase the stability and reach a temporal and spatial control of angiotensin-(1-9) release. Encapsulation efficiencies of nearly 50% were achieved in LipoTherm, reaching a total angiotensin-(1-9) loading of around 180 μM. This angiotensin-(1-9)-loaded LipoTherm sized around 100 nm and exhibited a phase transition temperature of 43 °C. AuNC were grown on LipoTherm and the new hybrid nanosystem showed energy absorption in the near-infrared (NIR) wavelength range. By NIR laser irradiation, a controlled release of angiotensin-(1-9) was achieved from the LipoTherm-AuNC nanosystem. These nanosystems did not show any cytotoxic effect on cultured cardiomyocytes. Biological activity of angiotensin-(1-9) released from the LipoTherm-AuNC-based nanosystem was confirmed using an ex vivo Langendorff heart model.

The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1–9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1–9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1–9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, angiotensin-(1–9) did not modify basal proliferation. However, angiotensin-(1–9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1–9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1–9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1–9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.

Angiotensin-(1-9) is a peptide from the noncanonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. In the present study we aimed to elucidate it, basing us initially on previous work from our group and colleagues who proved a relationship between disturbances in mitochondrial morphology and calcium handling, associated with the setting of cardiac hypertrophy. Our first finding was that angiotensin-(1-9) can induce mitochondrial fusion through DRP1 phosphorylation. Secondly, angiotensin-(1-9) blocked mitochondrial fission and intracellular calcium dysregulation in a model of norepinephrine-induced cardiomyocyte hypertrophy, preventing the activation of the calcineurin/NFAT signaling pathway. To further investigate angiotensin-(1-9) anti-hypertrophic mechanism, we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that PKA activity is necessary for the effects of angiotensin-(1-9) over mitochondrial dynamics, calcium handling and its anti-hypertrophic effects.

Resumen: Los modelos experimentales de falla cardíaca con fracción de eyección disminuida en murinos son pocos. Uno de estos modelos es el de coartación de la aorta torácica en el arco aórtico (COA) en ratones. Un aspecto importante en su desarrollo es la evaluación precoz del procedimiento y su relación con la función sistólica posterior. En este sentido, las velocidades de flujo carotídeo y la relación entre ambos flujos (derecho, pre-coartación; izquierdo post coartación) pueden permitir evaluar tempranamente la precisión del procedimiento y relacionarse más tardíamente con la función sistólica VI. Nuestro objetivo fue comparar precozmente (semana 2 post operatoria) las velocidades de flujo en ambas carótidas (Doppler continuo) y tardíamente (semana 5 postoperatoria) la función sistólica VI (Ecocardiograma de superficie) en ratones seudocoartados o sham (n= 6) vs ratones COA (n = 12). Se confirmó una diferencia estadísticamente significativa en la relación de velocidades de flujo entre ambas carótidas medida precozmente entre los ratones sham y COA (1,1 ± 0,1 vs 2,5 ± 0,5, p< 0,001), lo que se correlacionó con un deterioro significativo de la función sistólica del ventrículo izquierdo evaluada a las 5 semanas en los ratones COA. Conclusión: En este modelo preclínico de falla cardíaca por sobrecarga de presión con fracción de eyección VI disminuida en ratón, el aumento precoz de la velocidad de flujo en la arteria carótida derecha (pre-coartación en el modelo COA) y sobre todo de la relación entre las velocidades de flujo carotídeo entre ambas carótidas se asocia a deterioro importante de la función sistólica VI cinco semanas después de efectuada la COA, lo que permite predecir la efectividad del procedimiento en este modelo experimental.

Hypertension-induced cardiovascular and renal damage can be mediated by activation of the renin-angiotensin-aldosterone system. There are different factors beyond renin-angiotensin-aldosterone system involved in hypertension and renal damage. Inflammation has emerged as an important mediator of hypertension and cardiovascular and kidney damage. Angiotensin-(1-9), a peptide of the renin-angiotensin system, counter-regulates both the physiological and pathological actions of angiotensin II. Recent data has shown that angiotensin-(1-9) protects the heart and blood vessels from adverse cardiovascular remodeling in experimental models of hypertension and/or heart failure and reduces cardiac fibrosis in stroke-prone, spontaneously hypertensive rats. These effects are mediated by the angiotensin II type 2 receptor (AT2R). However, it remains unknown whether angiotensin-(1-9) also has an anti-inflammatory effect. In the present study, we investigate whether angiotensin-(1-9) reduces inflammation and fibrosis in the heart, arteries, and kidney in a DOCA-salt hypertensive model and explore the mechanisms underlying the amelioration of end-organ damage. DOCA-salt hypertensive rats received: a) vehicle, b) angiotensin-(1-9), c) PD123319 (AT2R blocker), d) angiotensin-(1-9) plus A779 (a Mas receptor blocker) or e) angiotensin-(1-9) plus PD123319, and sham rats were used as a control. Our results showed that angiotensin-(1-9) decreased hypertension and increased vasodilation in DOCA-salt hypertensive rats. These actions were partially inhibited by PD123319. Moreover, angiotensin-(1-9) decreased diuresis, fibrosis, and inflammation. These beneficial effects were not mediated by Mas or AT2R blockers. We concluded that angiotensin-(1-9) protects against volume overload-induced hypertensive cardiovascular and kidney damage by decreasing inflammation in the heart, aortic wall, and kidney, through mechanisms independent of the Mas or AT2R.

Angiotensin-(19), a peptide of the non-classical renin angiotensin system, has been shown to prevent and revert hypertension and cardiac hypertrophy. We hypothetized that systemic delivery of angiotensin-(1-9) following myocardial infarction will also be protective and extend to provide protection during reperfusion of the ischemic heart. Adult Sprague Dawley rats were subjected to left anterior descending artery ligation and treated with angiotensin-(1-9) via osmotic mini-pump for 2 weeks in the presence or absence of Mas receptor or AT2R antagonists (A779 and PD123319, respectively). Myocardial death and left ventricular function were evaluated after infarction. Infarct size and functional parameters were determined in isolated rat hearts after global ischemia/reperfusion in the presence of angiotensin-(1-9) plus receptor antagonists or Akt inhibitor at reperfusion. in vitro, neonatal rat ventricular cardiomyocytes underwent simulated ischemia/reperfusion and angiotensin-(1-9) was co-incubated with A779, PD123319 or Akt inhibitor. Systemic delivery of angiotensin-(1-9) significantly decreased cell death and improved left ventricular recovery after in vivo myocardial infarction. Perfusion with the peptide reduced the infarct size and improved functional recovery after ex vivo ischemia/reperfusion. In vitro, angiotensin-(1-9) decreased cell death in isolated neonatal rat ventricular cardiomyocytes subjected to simulated ischemia/reperfusion. The cardioprotective effects of angiotensin-(1-9) were blocked by PD123319 and Akti VIII but not by A779. Angiotensin-(1-9) limits reperfusion-induced cell death by an AT2R- and Aktdependent mechanism. Angiotensin-(1-9) is a novel strategy to protect against cardiac ischemia/reperfusion injury.

Left atrial (LA) contraction is essential for left ventricular (LV) filling during exertion. We sought to evaluate the relationship of LA contraction and exercise capacity in trained athletes. Sixteen male marathon runners were recruited and allocated into two groups according to their previous training status (≥ or

Background The intracellular ROCK signaling pathway is an important modulator of blood pressure and of cardiovascular and renal remodeling when Rho-kinase activity is increased. Besides, in preclinical models of diabetes, ROCK activation has also a role in abnormal glucose metabolism as well as in subsequent vascular and myocardial dysfunction. In humans, there are a few data assessing ROCK activation in patients with type 2 diabetes mellitus (T2D) and no studies assessing upstream/downstream components of the ROCK pathway. We assessed here levels of ROCK activation and some of the RhoA/ROCK cascade molecules in peripheral blood mononuclear cells (PBMCs) in T2D patients under current treatment. Methods Cross-sectional observational study comparing 28 T2D patients under current antidiabetic treatment with 31 consecutive healthy subjects, matched by age and gender. Circulating levels of malondialdehyde, angiotensin II and inflammatory cytokines IL-6 and IL-8 were determined in all subjects. ROCK activation in PMBCs, upstream and downstream cascade proteins, and levels of the proinflammatory molecules VCAM, ICAM-1 and IL-8 were determined in their PMBCs by Western blot. Results Compared to healthy controls, ROCK activation in T2D patients measured by 2 direct ROCK targets in PBMCs was increased by 420 and 570% (p Conclusions T2D patients under treatment with glucose-lowering drugs, antihypertensive treatment as well as with statins have significantly increased ROCK activation in their circulating leukocytes along with higher phosphorylation of downstream cascade proteins despite pharmacologic treatment, along with increased plasma angiotensin II and MDA levels. ROCK inhibition might have an additional role in the prevention and treatment of T2D.

Introduction Reports have shown increased risk of atrial fibrillation (AF) in athletes. Vascular cell adhesion molecule-1 (VCAM1) is associated with new onset AF in general population. VCAM1 and its relation with left atrial (LA) remodeling have not been investigated in athletes. Purpose To study VCAM1 and LA remodeling in marathon runners. Methods Study of 36 male marathon runners in the training period previous to race (42 km) and 18 sedentary controls with no risk factors. Athletes were divided in two groups according to highest training intensity reached (group 1, >100 km/week; group 2, 50–100 km/week). Previous to race in all subjects, VCAM1 serum levels were measured by ELISA and an echocardiogram was performed. In athletes, VCAM1 was measured immediately post-race. Wilcoxon and Spearman were used. Results See table. Group 1 showed a significant increment in VCAM1 post-race (651±350 to 905±373 ng/mL; p=0.002) as compared to group 2 with no increment (533±133 to 651±138 ng/mL; p=0.117). In athletes, a moderate correlation between LA volume and VCAM1 was found (rho: 0.483; p=0.007). Baseline characteristics Group 1 (n=18) Group 2 (n=18) Controls (n=18) p value Age (years) 37±6 38±5 36±4 0.373 Heart rate (bpm) 53±8 57±7 69±6 * 0.001 Body surface area (m2) 1.8±0.1 1.8±0.1 1.9±0.1 0.075 LV diastolic diameter (mm) 49±5 48±5 46±4 0.404 LV systolic diameter (mm) 29±5 30±5 30±4 0.879 Septal wall (mm) 9.1±1.2† 8.2±1.1 8.1±0.8 0.005 Posterior wall (mm) 9.3±2.1† 8.5±1.2 7.6±0.8 0.001 Ejection fraction (%) 55±3 55±6 57±4 0.110 LV mass index (g/m2) 106±27† 78±18 58±11 0.001 LA volume (mL/m2) 42±8† 30±11 25±9 0.001 E wave (cm/sec) 78±13 84±12 77±15 0.217 A wave (cm/sec) 50±12 53±10 48±16 0.438 DT (msec) 233±65 229±65 221±66 0.184 VCAM1 (ng/mL) 651±350† 533±133 440±98 0.022 Mean ± SD. *p Conclusions Most trained athletes had increased levels of VCAM1 as compared to controls and less trained athletes. They also showed an increment post-effort. VCAM1 is related to LA remodeling in athletes. VCAM1 could be a potential biomarker of AF in athletes which should be confirmed. Acknowledgement/Funding FONDECYT 1170963 (LG); FONDAP 15130011 (LG,SL)

The renin&ndash, angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the anti-metastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDA-MB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.

Resumen: Introducción: La vía clásica del sistema renina-angiotensina (SRA) está activado en pacientes con hipertensión arterial pulmonar (HAP). Previamente, hemos encontrado que en la disfunción ventricular post infarto al miocardio experimental la activación del eje clásico del SRA, dado por la enzima convertidora de angiotensina I (ECA) y angiotensina (Ang ) II se correlaciona negativamente con el eje paralelo del SRA dado por la ECA homóloga (ECA2) y el péptido vasoactivo y cardioprotector Ang-(1-9). Resultados preclínicos muestran la eficacia de la administración de Ang-(1-9) en el tratamiento del remodelamiento cardiovascular patológico. Hasta la fecha no existen antecedentes de los niveles circulantes de Ang-(1-9) en pacientes con hipertensión arterial pulmonar comparados con sujetos sanos. Objetivo: Determinar los niveles circulantes del péptido vasoactivo y cardiprotector Ang-(1-9) en pacientes con HAP y compararlos con sujetos sanos pareados por edad y sexo. Métodos: Estudio comparativo transversal en pacientes con HAP (grupo I, OMS) con presión de arteria pulmonar media (mPAP) ≥25 mmHg bajo tratamiento con furosemida (40%), espironolactona (53%), Acenocumarol/Warfarina (47%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) y digoxina (13%). Los sujetos controles correspondieron a sujetos asintomáticos sanos sin enfermedad cardiovascular, cardiopatía estructural ni pulmonar (n=14). En todos los pacientes se determinó mPAP, proBNP, resistencia vascular pulmonar (RVP, WU), presión capilar pulmonar (PCP, mmHg), gasto cardíaco (L/min), capacidad funcional por test de caminata 6 minutos (TC6M), cambio del área fraccional del ventrículo derecho VD (FAC, %). Se utilizó prueba t de Student y programa estadístico SPSS10.0. Un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: Los pacientes ingresados al estudio mostraron: etiología de la HAP, idiopática (86,7%), VIH (13,3%), capacidad funcional I (6,2%), II (68,3) y III (25%) y promedio mPAP 51,3±1,9. Pacientes con HAP (grupo I, OMS) versus sujetos sanos mostraron disminución significativa de FAC, actividad plasmática de la ECA2 y niveles circulantes de Ang-(1-9). En la vía clásica del RAAS pacientes con HAP mostraron mayor actividad plasmática de ECA y niveles circulantes e Ag II. Correlaciones significativas se encontraron entre niveles de Ang-(1-9) y mPAP (r = -0.701, p < 0,001) y Ang-(1-9) vs FAC (r = 0.549, p < 0,01). Conclusiones: En pacientes con HAP (grupo I, OMS), los niveles circulantes de Ang-(1-9) están significativamente disminuidos y se asocian inversamente con la PAP, severidad del remodelamiento y disfunción del ventrículo derecho. El uso terapéutico de Ang-(1-9) como agente vasodilatador y cardioprotector podría ser relevante y potencialmente útil, desde una perspectiva clínica, en la HAP. Ang-(1-9) podría reducir la PAP y mejorar el remodelamiento vascular y del ventrículo derecho en la HAP. Por lo tanto, este péptido podría ser útil como blanco terapéutico en la HAP.

The renin–angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II — initially thought to be biologically inactive — have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin–angiotensin system consists of angiotensin 1–7, angiotensin 1–9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT2R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin–angiotensin system. This counter-regulatory renin–angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin–angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease., The non-canonical axis of the renin–angiotensin system (RAS) has an important role in cardiovascular physiology and disease. In this Review, Ocaranza and colleagues discuss the interplay between components of the counter-regulatory RAS and the therapeutic potential of targeting this system to treat cardiovascular disease., Key points Chronic activation of the renin–angiotensin system (RAS) promotes cardiovascular damage, an effect that is antagonized by components of the counter-regulatory RAS.Components of the counter-regulatory RAS, including angiotensin 1–7, angiotensin 1–9, alamandine and their receptors have been found to be protective in multiple cardiovascular diseases, such as hypertension and heart failure.Numerous preclinical studies have demonstrated the beneficial effects of the counter-regulatory RAS, but clinical trials confirming these observations are still scarce.The challenges in quantitating angiotensin 1–7, angiotensin 1–9 and alamandine associated with their short plasma half-life and similarity in their molecular structures must be overcome before these peptides can be evaluated in the clinical setting.

AIMS Two-dimensional speckle-tracking echocardiography can assess left atrial (LA) function by measuring atrial volumes and deformation parameters (strain, strain rate). This cross-sectional analysis explores the association between ideal CV health (CVH), LA function, and systemic biomarkers in healthy individuals from the Chilean MAUCO Cohort. METHODS We enrolled 95 MAUCO participants with different levels of CVH (mean age: 51 ± 8 years). We categorized participants into low or high CVH groups: A: 0-2, or B: 3-6 CVH risk factors. 2D echocardiography, glucose, insulin, total cholesterol, triglycerides, proBNP, hsCRP, insulin resistance index (HOMA), and right and left atrial strain (RASs and LASs, respectively) were determined. RESULTS LASs was lower in Group A, while systolic and diastolic blood pressure (BP), body mass index (BMI), insulin, HOMA, total cholesterol, triglycerides, and LV and RV end-diastolic volume were significantly higher in Group A than Group B (P

Background: Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats. Methods: Deoxycorticosterone acetate (DOCA)-salt hypertensive rats (male, Sprague–Dawley) were randomized to the specific ROCK inhibitor FAS, HCTZ, spiro or the combinations of FAS/HCTZ or FAS/spiro for 3 weeks. At the end of the study, ROCK activation (by western blot), gene expression of proremodeling markers (by reverse transcription polymerase chain reaction, RT-PCR) and vascular hypertrophy (by morphometry) were determined in the aortic wall. Results: All treatments significantly reduced blood pressure. In the DOCA rats the p-myosin phosphatase target protein-1 (MYPT1)/t-MYPT1 ratio, index of ROCK activation was higher by 2.8 fold ( p < 0.05) compared with control rats. All treatments reduced ROCK activation in the aortic wall to control levels ( p < 0.05). Besides, significantly increased protein levels of transforming growth factor β1 (TGF-β1), gene expression of TGF-β1, connective tissue growth factor (CTGF), p22 phox and gp91 phox subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as well as increased media thickness and aortic media area/lumen area (AM/LA) in the untreated hypertensive rats were significantly reduced ( p < 0.05) to control levels by all treatments. Similar effects were observed using both diuretics alone or in combination with FAS. Conclusions: In the aortic wall, both HCTZ and spiro in antihypertensive doses reduce ROCK activation, subsequent expression of genes that promote vascular remodeling and hypertrophy in this experimental model of hypertension. These effects could explain some of their clinical benefits in hypertensive patients.

The small guanosine triphosphatase RhoA and its direct target Rho kinase (ROCK) play important roles in cardiovascular pathophysiology. Activated ROCK phosphorylates intracellular proteins with detrimental effects on cardiovascular remodeling. Increased ROCK activity in circulating leukocytes is observed in hypertension and in heart failure, but its relationship with ROCK activation in the myocardium and vessels is unknown. We hypothesized that ROCK activation and phosphorylation/activation of some of its key downstream molecules in the heart and arterial wall are reflected in circulating leukocytes.Phosphorylation of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were determined in the left ventricle (LV), aortic wall and circulating leukocytes in rats with high (Brown Norway, BN) and low (Lewis) angiotensin converting enzyme. A group of BN rats received the ROCK inhibitor fasudil (7days).Compared to Lewis rats, in the BN group phosphorylated levels of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were increased (P0.05) in the LV (67%, 92%, 52% and 98%, respectively); in the aortic wall (57%, 51%, 68% and 66%, respectively) and in circulating leukocytes (61%, 72%, 49% and 105%, respectively). Fasudil reduced all these levels to those observed in Lewis rats. Phosphorylated MYPT1, ERM, and p38-MAPK and levels of p65-NF-κB in circulating leukocytes were significantly correlated with their respective LV and aortic wall levels (excepting p65-NF-κB in aorta).ROCK activity in circulating leukocytes reflects activation of this signaling pathway in the myocardium and aortic wall in this model, and supports its value as a potential cardiovascular remodeling marker.

Background: Pulmonary arterial hypertension (PAH) is a rare and progressive disease. Long-term survival remains poor despite of advances in specific vasodilator therapy. Aim: To describe the survival rate in a cohort of PAH patients in two referral centers in Chile. Patients and methods: One hundred fifteen patients aged 43 ± 15.6 years (85 % females) with PAH qualified for this study. Their median pulmonary artery pressure was 55.4 ±14 mm Hg and their six minutes walking capacity was 368 ± 119 m. They were followed for 58 ± 0.4 months and their actual survival rates were compared with the estimated survival using the equation proposed by the French registry of PAH. Results: One, two and three year survival rates were 97, 94 and 89%, respectively. The observed survival rates were greater than the estimated survival. Conclusions: The improvement in survival rates observed in this cohort of patients is similar to what has been described in literature.

Resumen: Introducción: El ejercicio físico reduce la mortalidad cardiovascular y genera remodelado cardíaco. Altas cargas de entrenamiento pueden generar remodelado cardíaco adverso. Biomarcadores (BMC) de inflamación Interleukina 6 (IL-6) y de estrés oxidativo Malondialdehído (MDA), potencialmente pueden caracterizar la respuesta al esfuerzo. Objetivo: Evaluar actividad de IL-6 y MDA en respuesta a una maratón en atletas con distinto nivel de entrenamiento y remodelado cardíaco asociado. Sujetos y Métodos: Estudio prospectivo, simple ciego, incluyó 16 atletas que completaron la maratón de Santiago (42 k), separados según entrenamiento previo, grupo 1 (G1, n: 8): Alto ≥ 100 km/semana y grupo 2 (G2, n: 8): Bajo

Moderate endurance exercise has long been considered an essential element to maintain cardiovascular health, and sedentary behaviour in the general population has been related to a significant increase in all-causes of mortality, cardiovascular disease mortality and cardiovascular disease incidence. However, a growing group of people performs an intense exercise that leads to multiple heart adaptive changes that are collectively called "athlete's heart". In this review, we discussed the evidence of cardiac remodelling process secondary to repetitive and strenuous exercise in some predisposed athletes that produces intense and probably deleterious changes in cardiac morphology and function with no clear clinical significance in long-term follow-up. Moreover, we also discussed the individual biological response to exercise assessed by myocardial damage, inflammation, oxidative stress, fibrosis and ventricular hypertrophy biomarkers showing different intensities with equivalent exertion.

Rho-kinase has relevant functions in blood pressure modulation and cardiovascular remodeling. Rho-kinase activity is determined in circulating leukocytes measuring phosphorylation of its target myosin phosphatase target subunit 1 (MYPT1), but its relationship with Rho-kinase activity in the myocardium and in vasculature in hypertension has not been evaluated. The aim was to determine the degree of association between Rho-kinase cascade activation in circulating leukocytes with cardiac and aortic Rho-kinase pathway activation in a model of hypertension and to analyze it with a cause–effect perspective. Hypertensive deoxycorticosterone (DOCA)-salt rats received the Rho-kinase antagonist fasudil (DOCA-Fas, 100 mg/kg/day, 3 weeks). Results were compared with an untreated DOCA-salt and a sham group. Rho-kinase inhibition reduced significantly blood pressure, cardiac hypertrophy, myocardial collagen and macrophage infiltration, but not aortic wall hypertrophy. Fasudil decreased significantly Rho-kinase activity in peripheral blood mononucleated cells (PBMC), myocardium and aortic wall to similar levels as in the sham group. A significant correlation was found between PBMC Rho-kinase activity and cardiac remodeling, specifically with hypertrophy (r = 0.51, P≤0.01), myocardial collagen (r = 0.40, P≤0.05) and ED1 immunostaining (r = 0.48, P≤0.01). In the untreated hypertensive group, increased levels (P In conclusion, in this hypertension model, Rho-kinase and its pathway activation determined in circulating leukocytes reflect the activation of this pathway in the myocardium and in the aortic wall and are significantly related to myocardial remodeling (hypertrophy, fibrosis and inflammation).

Introduccion: En pacientes con hipertension arterial pulmonar (HAP) Galectina- 3, biomarcador de fibrosis miocardica, se ha asociado a marcadores ecocardiograficos de remodelado ventricular derecho. La relacion entre Galectina- 3, remodelado auricular derecho (AD) y capacidad funcional (CF) en pacientes con HAP no ha sido explorado. El objetivo fue medir niveles de Galectina-3 y su relacion con CF y remodelado AD en pacientes con HAP Metodos: Estudio prospectivo observacional en que se incluyeron 14 pacientes con HAP En todos los pacientes se midieron los niveles de Galectina-3, proBNP, se evaluo la CF mediante test de caminata 6 minutos (TC6M) y se evaluo remodelado AD. Se consideraron para el analisis dos grupos segun la distancia caminada en TC6M (> 200 m vs. ≤ 200 m). Resultados: La edad promedio fue 43 ± 10 anos, el 84% mujeres. Los niveles de Galectina-3 fueron 16,1 ± 7,4 ng/mL y el TC6M fue 371 ± 142 mts. Los pacientes con TC6M< 200 m presentaron mayores niveles de Galectina-3 (27,3 ± 4,6 vs 13,7 ± 3,8; p=0,006) y mayor volumen AD (151 ± 21 vs 94 ± 43; p=0,04). Ademas, se observo una correlacion inversa entre el area AD y TC6M (-0,71; p=0,03). Conclusion: Niveles elevados de Galectina-3 y parametros de remodelado adverso en AD se relacionan con una menor CF en pacientes con HAP. Estos hallazgos apuntan a una mejor caracterizacion de pacientes con HAP y eventualmente la busqueda de nuevos objetivos terapeuticos.

Objective: The objective of this study was to determine the molecular mechanisms by which cardiac Rho-associated coiled-coil containing protein kinase (ROCK) activation after myocardial infarction (MI) does intervene in cardiac systolic function decline and remodeling. Methods: Simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis and hypertrophy in rats with MI under ROCK inhibition with fasudil. Results: Seven days after MI, the ventricular mass increased significantly by 5.6% in the MI group and was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, cardiomyocyte ROCK2 fluorescence levels and β-myosin heavy chain (MHC) levels in addition to myocardial collagen volume fraction decline. Compared with sham rats, troponin phosphorylation levels after MI were similar and ROCK inhibition reduced them. MI significantly increased phosphorylation levels of extracellular-signal-regulated kinase (ERK) 42 and ERK 44 by twofold and 63%, respectively, whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 and the ROCK inhibitor normalized them. Conclusions: LV systolic dysfunction after MI was strongly associated with cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling such as β-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis and normalized β-MHC and ERK/GATA-4 phosphorylation levels.

The renin–angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE–Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

Introduccion: Angiotensina (Ang)-(1-9) posee propiedades anti-hipertensivas y efecto protector a nivel cardiovascular en ratas hipertensas. Sin embargo, se desconoce si estos efectos estan asociados a un mecanismo de desbalance de sodio a nivel renal. Objetivo: Determinar si el efecto anti-hipertensivo de Ang-(1-9) esta asociado a un mecanismo diuretico-na-triuretico. Metodo: Ratas macho Sprague Dawley (200 ± 10g) fueron aleatorizadas para recibir Ang II (400 ng/kgmin) via bomba osmotica. Como control se utilizaron ratas con operacion sham (n=18). Despues de 2 semanas desde la instalacion de bomba, las ratas Sham e hipertensas fueron randomizadas para recibir vehiculo (n=10), Ang-(1-9) (602 ng/kg/min, n=17) o una co-administracion de Ang-(1-9) y A779 (100 ng kg-1min-1, n=7 bloqueador del receptor MAS) por 2 semanas. Resultados: Se determino la presion arterial sistolica (PAS), masa ventricular relativa (MVR), area y perimetro de los cardiomiocitos (AC y PC) y la fraccion volumetrica de colageno total (FVCT). Para evaluar la diuresis y natriuresis se utilizaron ratas normotensas que fueron randomizadas para recibir vehiculo (n=8) o Ang-(1-9) (600 ngKg-1min-1, n=8) por 6 dias. Se observo un incremento significativo(p

Resumen: Objetivo: Determinar algunos mecanismos moleculares por los cuales la activación de ROCK cardíaca post infarto del miocardio (IAM) participa en el remodelado y en deterioro de la función sistólica. Métodos: Determinación simultánea de niveles de proteínas blanco de ROCK cardíaca, de función sistólica in vivo del ventrículo izquierdo (VI) y de fibrosis e hipertrofia cardíaca en ratas con IAM en condiciones de inhibición de ROCK con fasudil. Resultados : Siete días post IAM la masa ventricular relativa aumentó significativamente en un 30% en el grupo MI y se redujo con fasudil. La disfunción sistólica VI mejoró significativamente con fasudil mientras que la activación de ROCK cardíaca se redujo a niveles del grupo control. El inhibidor de ROCK también redujo significativamente los niveles cardíacos elevados de las isoformas ROCK1 y ROCK2, de MHC-β y del colágeno miocárdico. En el grupo con IAM aumentaron significativamente los niveles de fosforilación de ERK 42 y ERK 44 (en 2 veces y en 63%, respectivamente), mientras que en el grupo IAM tratado con fasudil estos niveles fueron similares a los del grupo control. El IAM aumentó significativamente los niveles fosforilados del factor de transcripción GATA-4, que se normalizaron con el inhibidor de ROCK. Conclusiones: La disfunción sistólica post IAM se asoció fuertemente con la activación del ROCK cardíaca y con la fosforilación de proteínas río abajo de ROCK que promueven remodelado cardíaco como β-MHC y la vía ERK / GATA-4.

Major challenges in heart failure with reduced ejection fraction (HFrEF) are promotion of reverse cardiac remodeling and development of specific biomarkers. Activation of the Rho kinase (ROCK) signaling pathway in HFrEF patients is associated to myocardial remodeling and LV dysfunction. Besides

BACKGROUND There is experimental evidence on the role of Rho-kinase (ROCK) activation in cardiac hypertrophy but no information on its role in human hypertension and left ventricular hypertrophy (LVH). We hypothesized that ROCK activity is higher in hypertensive patients with LVH compared with hypertensive patients without LVH. METHODS We conducted a cross-sectional study comparing untreated hypertensive patients with (n = 41) and without LVH (n = 46) determined by echocardiography with a healthy normotensive control group (n = 51). Measurements included LV mass, dimensions, and function and ROCK activity determined in circulating leukocytes by measuring Western blot levels of phosphorylated to total myosin light chain phosphatase 1 (MYPT1-p/t). RESULTS Compared with normotensive subjects, MYPT1-p/t was significantly increased by 4.5-fold in the hypertensive patients without LVH and by 9-fold in the hypertensive patients with LVH. Compared with the hypertension without LVH group, MYPT1-p/t was significantly increased by 2-fold in the hypertension with LVH gorup. In patients with eccentric LVH, the mean MYPT1-p/t ratio was significantly higher by 4-fold compared with hypertensive patients without eccentric LVH. Patients with an E/e' ratio ≥15 (n = 6) showed a higher MYPT1-p/t ratio (by 26%) compared with patients with a lower E/e' ratio (P ≤ 0.01). CONCLUSIONS ROCK activity is higher in hypertensive patients with LVH compared with hypertensive patients without LVH, and it is further increased when eccentric LVH is present. Thus, in hypertension, ROCK activation is related to pathological cardiac remodeling and might have a role as an LVH marker.

Previamente hemos demostrado que la eficacia de enalapril, candesartán y de fasudil -inhibidor de la vía RhoA/ROCK,- en el tratamiento del remodelado cardíaco en la hipertensión (HTA) e infarto al miocardio está mediada por aumento en los niveles circulantes del péptido vasoactivo angiotensina [Ang]-(1-9). Sin embargo, no hay información disponible si el antagonista del receptor de mineralocorticoide, espironolactona (espiro) disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9). El objetivo de este trabajo fue determinar si espironolac-tona disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9) en la hipertensión arterial experimental. Métodos. Estudio comparativo de 3 grupos experimentales. Se utilizaron ratas Sprague Dawley macho (150 ± 10 grs) unifrectomizadas tratadas con desoxi-corticosterona (DOCA, 60mg/Kg 2 veces sem, im) por 6 semanas. Como controles (Sham) se usaron ratas unifrectomizadas. A partir de la 3° semana las ratas DOCA con HTA> 140 mmHg fueron randomizadas a recibir vehículo o espiro (100 mg/kg día, gavage) por 3 sem. Al finalizar el tratamiento se determinó la presión arterial sistólica (PAS), masa corporal, peso del corazón (PC) y masa cardíaca relativa al largo de la tibia (MCR, mg ventrículos/LT*100). El grado de hipertrofia car-diomiocitaria se determinó midiendo el área y perímetro de los cardiomiocitos y la fibrosis por el contenido de colágeno en cortes teñidos con rojo picrosirio. Resultados (promedio ± ES): Conclusión: Espironolactona disminuye la PAS y aumenta los niveles circulantes de Ang-(1-9). Este aumento en los niveles circulantes de Ang-(1-9) se asocia con una disminución significativa de la hipertrofia y la fibrosis cardiaca hipertensiva. Este nuevo efecto de espironolactona en los niveles circulantes de Ang-(1-9), - péptido vasoactivo de la vía paralela del sistema renina-angiotensina-aldosterona,- podría contribuir al efecto antihipertensivo y disminución del daño cardiaco en la hipertensión y remodelamiento cardiovascular y renal patológico. Estos hallazgos pueden tener relevancia terapéutica en términos que Ang-(1-9) podría disminuir el daño cardiovascular patológico.

BACKGROUND Right atrium function and ventricular function have significant prognostic value in pulmonary arterial hypertension patients. Acute changes in right ventricular synchrony and right atrium function postiloprost inhalation have not been evaluated. METHODS Cross-sectional study. Consecutive pulmonary arterial hypertension patients (group I from Nice classification) were included. Echocardiographic right atrium and right ventricular function pre- and postiloprost inhalation, including a right ventricular dyssynchrony index and right atrium function using speckle tracking, were performed in all patients. RESULTS Twenty pulmonary arterial hypertension patients, 44±7 years and 90% females, were included. After iloprost inhalation, we observed a significant increment in right ventricular fractional area change and a significant decrease in right ventricular dyssynchrony index (21.4±5.6% vs 26.1±4.0 %, P=.007 and 79±44 vs 32±22 mseconds, P

See related article, pp 630–641 During the past 40 years, most of the new developed and effective antihypertensive drugs target the classic renin–angiotensin–aldosterone system (RAAS) by blocking receptors (such as the mineralocorticoid receptor or the angiotensin II type 1 receptor) and also by inhibiting enzymes within the angiotensin II (Ang II) formation pathway, such as the angiotensin-converting enzyme I (ACE I) and renin as well. More recently, a different group of targets within the RAAS has been explored as antihypertensive molecules. This parallel RAAS has been described as the natural vasodilatory and counterregulatory pathway of the RAAS. By year 2000, this pathway was discovered consisting of ACE2, angiotensin 1–9 (Ang1–9), Ang-(1–7) and recently, alamandine. These endogenous molecules display biological effects opposed to Ang II; thus, their activation induces vasodilation, blood pressure reduction, antihypertrophy, and antihyperplasia, suggesting a plausible antihypertensive role of this axis. In this issue of Hypertension , the role of dipeptidyl peptidase III (DPP III) as a new antihypertensive candidate has been characterized in the mice.1 Similar to DPP III, the carboxy peptidase ACE2 mediates degradation from Ang II to Ang (1–7) and also from Ang I to Ang (1–9). Both peptides contribute to the antihypertensive/vasoprotective effects of the counterregulatory RAAS pathway (Figure). Interest in ACE2 as a therapeutic target has led to the synthesis of small ACE2 activator molecules, which lower blood pressure, improve myocardial function, and reverse myocardial and perivascular fibrosis in the sponstaneously hypertensive rat. As an alternative to pharmacological ACE2 activation, recombinant human ACE2 has been shown to lower blood pressure in experimental hypertension. A phase I study in healthy volunteers demonstrated sustained (>24 hours) suppression of circulating Ang II levels after a single intravenous injection of …

Cardiovascular disease is the leading cause of death worldwide. The heart is susceptible to pathologies that impact the myocardium directly, such as myocardial infarction and consequent heart failure, as well as conditions with indirect cardiac effects, such as cancer treatment-related cardiotoxicity. As the contractile cells of the heart, cardiomyocytes are essential for normal cardiac function. Various stress stimuli may result in transient damage or cell death in cardiomyocytes through apoptosis, necrosis or maladaptive autophagy. Moreover, cardiomyocytes are unable to regenerate; thus, lost cells are replaced with fibrotic tissue, with a potentially severe impact on myocardial function. Several therapeutic agents and strategies to reduce cardiomyocyte damage are currently available. This manuscript reviews the state of the art regarding novel cardioprotective endogenous peptides, such as neuregulin-1, angiotensin-(1-9), growth/differentiation factor-11, growth/differentiation factor- 15 and insulin-like growth factor-1. We discuss their protective effects and therapeutic potential in cardiovascular diseases and the current challenges to harnessing their full cardioprotective power. We also explore targeting of exosomes as a cardioprotective approach along with the therapeutic potential of cardiac regeneration strategies. Further advances associated with these molecules and cardioprotective approaches may provide more effective therapies to attenuate or prevent cardiomyocyte death, thereby preserving the myocardium.

Resumen: La enzima convertidora de angiotensina I (ECA2) a través de Angiotensina (Ang)-(1-9) más que Ang-(1-7) contrarresta los efectos deletéreos de ECA y Ang II. Se desconoce si Ang-(1-9) es efectiva en el tratamiento del remodelamiento cardiovascular (RMCV) hipertensivo, en ratas con polimorfismo del gen de la ECA. Objetivo: Determinar el efecto de Ang-(1-9) en el tratamiento del RMCV hipertensivo en ratas con niveles genéticamente determinados de ECA y Ang II. Métodos: Ratas normotensas homocigotas, Lewis (LL) y Brown Norway (BN), se les indujo HTA a través del modelo Goldblatt (GB, 2 riñones-1 pinzado). Después de 4 semanas, las ratas hipertensas se rando-mizaron para recibir Ang-(1-9) (602 ng/Kg min) o una coadministración de Ang-(1-9)+A779 (100 ng/Kg min, antagonista del receptor MAS de Ang-(1-7)) durante 14 días mediante una minibomba. Como controles se usaron ratas sometidas a operación ficticia (Sham). Se determinó masa corporal (MC), presión arterial sistólica (PAS), masa ventricular (MV), área de cardiomiocitos (AC), área y grosor de la túnica media (ATM, GTM), fracción volumétrica de colágeno total (FVCT) en el ventrículo izquierdo (VI), niveles proteicos de colágeno tipo I (Col I) en la aorta (Ao) y la infiltración de macrófagos en Ao y VI, por medio de su molécula especifica ED1 (ED1-Ao, ED1-VI). Resultados: La administración de Ang-(1-9) disminuyó significativamente PAS, MV, AC, FVCT, Col I, ATM, GTM, ED1-Ao (-) y ED1-VI, en las ratas hipertensas LL y BN respecto a las ratas GB sin tratamiento, respectivamente. Este efecto no fue inhibido por el antagonista A779. El polimorfismo de la ECA no modificó la respuesta al tratamiento. Conclusión: Ang-(1-9) redujo eficazmente la HTA y el RMCV secundario, independiente al polimorfismo en el gen de la ECA. Este efecto posiblemente es directo ya que no fue mediado por Ang-(1-7). Fondecyt 1100874.

Introducción: El polimorfismo del gen de la enzima convertidora de angiotensina I (ECA) determina mayor actividad de la ECA y mayores niveles de angioten-sina (Ang) II. Un polimorfismo similar ha sido descrito en humanos. La ECA2, a través de Ang-(1-9) más que Ang-(1-7), contrarresta los efectos deletéreos de Ang II. Se desconoce si el polimorfismo de la ECA frente a un estímulo hipertensivo modifica el eje ECA2/Ang-(1-9) y determina mayor remodelamiento de la pared aórtica de ratas hipertensas. Objetivo: Determinar el efecto del polimorfismo del gen de la ECA en la actividad del eje ECA2/Ang-(1-9) y su efecto en el remodelamiento de la pared aórtica secundaria a la hipertensión arterial (HTA) experimental. Métodos: Se usaron ratas macho homocigotas de 150 gr BN y LL. Se indujo HTA por el procedimiento Goldblatt (GB, 2 K-1clip). Ratas pseudo-operadas se usaron como controles (Sham). A las 6 semanas post cirugía se determinaron en la aorta las actividades de ECA y ECA2, los niveles de Ang II/Ang-(1-9), colágeno tipo I, células positivas para el marcador de inflamación ED-1, área y grosor de la túnica media (ATM, GTM). Resultados: El polimorfismo de la ECA con mayores niveles de ECA y Ang II determinó una mayor disminución de la actividad de ECA2, menores niveles de Ang-(1-9) y mayor remodelamiento de la pared aórtica tanto en animales normotensos como hipertensos. Conclusión: El polimorfismo de la ECA con mayor actividad de ECA y AngII determina una interregu-lación de los ejes ECA/AngII y ECA2/Ang-(1-9) lo que se asocia a mayor remodelamiento de la pared aórtica. Fondecyt 1100874.

Angiotensin II (Ang II) levels depend on renin, angiotensin-converting enzyme (ACE), and on the homologous angiotensin-converting enzyme (ACE2). Increased ACE and Ang II levels are associated with higher Rho kinase activity. However, the relationship between Rho kinase activation and ACE2 in hypertension is unknown.The role of the Rho kinase signaling pathway in both enzymatic activity and aortic gene expression of ACE2 in deoxycorticosterone acetate (DOCA) hypertensive rats was assessed in the present study.Compared with sham animals, Rho kinase activity was higher by 400% (P0.05) in the aortic wall of the DOCA hypertensive rats. In addition to blood pressure reduction, the specific Rho kinase inhibitor fasudil reduced aortic Rho kinase activity to levels observed in the sham control group and increased ACE2 enzymatic activity (by 83% in plasma and by 52% in the aortic wall, P0.05), ACE2, and endothelial nitric oxide synthase (eNOS) aortic mRNA levels (by 340 and 40%, respectively, P0.05) with respect to the untreated hypertensive DOCA rats. Fasudil also increased significantly plasma levels of Ang-(1-9) in normotensive and in the hypertensive rats. Aortic mRNA and protein levels of transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor 1 (PAI-1), and monocyte chemoattractant protein 1 (MCP-1) were significantly (P0.05) higher in the untreated DOCA rats and were normalized by fasudil administration.In experimental hypertension, Rho-associated, coiled-coil containing protein kinase (ROCK) inhibition reduces blood pressure and increases ACE2 levels and activity. At the same time, ROCK inhibition reduces angiotensin II and increases Ang-(1-9) plasma levels. Fasudil also increases vascular eNOS mRNA levels and reduces aortic overexpression of the remodeling promotion proteins TGF-β1, PAI-1, and MCP-1. This effect might additionally contribute to the antihypertensive and antiremodeling effects of ROCK inhibition in hypertension.

Antecedentes: En la isquemia/reperfusión (IR) miocárdica es relevante la pérdida de cardiomiocitos por apoptosis. En estos, los hemicanales (HC) permiten el ingreso de sustancias proapoptóticas durante la IR. Boldina (B), compuesto extraído del Peumus boldus, ha demostrado ser antioxidante y bloquear los HC. Objetivo: Determinar el efecto de boldina sobre la apoptosis de cardiomiocitos de ratas sometidas a IR. Métodos: Ratas macho de 200 g de peso se sometieron a ligadura reversible de la arteria coronaria izquierda por 30 minutos (I) y posterior reperfusión (R) por 24 horas post I. Un subgrupo de estos animales recibió una dosis de boldina intraventricular (IR+B, 40 mg/Kg) y luego dos dosis vía gavage (75 mg/Kg) a los 30 y 60 minutos post-R. Como controles se usaron ratas sham con operación ficticia, que recibieron igual tratamiento. Se determinaron las masas corporal (MC) y cardiaca relativa (MCR) y presión arterial sistólica (PAS). Porcentaje de cardiomiocitos apoptóticos (CMAP), otras células apoptóticas (OCAP) y total de células apoptóticas (TCAP) se determinó por TUNEL. La activación de metaloproteinasas (MMPs) 2 y 9 se determinó por zimografía y el mRNA de MCP-1 por RT-PCR. Resultados: La boldina no modificó la MC y la MCR. Sin embargo, disminuyó significativamente la PAS así como el %CMAP y el %TCAP en el grupo IR+B versus IR (CMAP 69 ± 1,5 vs 44 ± 0,4, p=0,016, TCAP 71 ± 2,4 vs 57 ± 1,5, p=0,016). No se encontraron diferencias en el OCAP, actividad de MMPs y en los niveles de mRNA de MCP-1. Conclusiones: Boldina disminuyó la PAS y la apoptosis de cardiomiocitos post IR. Su efecto no es mediado por modificaciones en la actividad de MMPs y expresión génica de MCP-1.