Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Asociación de los niveles de glucemia con la hipertrofia miocárdica / Association between plasma glucose concentrations and myocardial hypertrophy

La aparición de hipertrofia cardíaca está mediada tanto por factores hemodinámicos como por factores no hemodinámicos. En este sentido, se ha descrito una relación positiva y significativa entre la masa ventricular izquierda (MVI) y la hemoglobina A1c en la hipertensión esencial. Además, los individuos hipertensos con diabetes tienen una mayor MVI que los pacientes no diabéticos hipertensos, pese a tener cifras de presión arterial similares. También se ha descrito que una mejora del control glucémico contribuye a la regresión de la hipertrofia ventricular izquierda en pacientes hipertensos con diabetes tipo 2, y que estos cambios se produjeron de forma independiente de la variación de la presión arterial. Por último, se ha publicado recientemente que “la efectividad de la glucosa” (que representa la capacidad de la glucosa para llevar a cabo por sí misma su propia desaparición en plasma, con independencia de los cambios dinámicos de la insulina basal) está fuertemente relacionada con la MVI en pacientes con hipertensión estadio 1 o con cifras de presión arterial normal-alta.

La sobreexpresión del gen de enzima convertidora de angiotensina homóloga (ECA2) revierte la hipertensión arterial y el remodelado cardíaco experimental / Over expression of the homologous angiotensin converting enzyme (ACE2) gene reverts experimental hypertensión and cardiac remodeling

Antecedentes: La sobreexpresion génica de la enzima convertidora de angiotensina I homologa (ECA2) se asocia con prevención de la hipertrofia y fibrosis cardiaca dependiente de angiotensina (Ang) II. Sin embargo se desconoce si su sobreexpresion reduce la hipertensión arterial (HTA) y revierte el consecuente remodelado miocárdico (RM) dependiente de Ang II. Objetivo: Determinar si la sobreexpresion adenoviral (Ad) del gen de la ECA2 en el miocardio disminuye la HTA y RM experimental en ratas con niveles genéticamente determinados de ECA y Ang II. Métodos: Ratas homocigotas normotensas Lewis (LL) y Brown Borway (BN), con menores y mayores niveles circulantes de ECA y Ang II, respectivamente, se hicieron hipertensas por el procedimiento Goldblatt (GB). Como controles se usaron ratas seudo-operadas (sham). A la semana 5 post cirugía y con HTA establecida > 140 mmHg, las ratas se randomizaron a inyección intramiocárdica con un AdECA2 o Ad proteína fluorescente verde (GFP) como controles de infección. A la semana post infección adenoviral, los ratas se sacrificaron y se determinaron peso corporal (PC, g), masa cardiaca (MC, mg), presión arterial sistólica (RAS, mmHg), área (AC, um2) y perímetro (PERC, um) de cardiomiocitos y contenido de colágeno ( por ciento) miocárdico (CM), sub-endocárdico (CS)ytotal(CT). Resultados: La HTA aumentó significativamente la MC, MCR, AC, PERC como también el CM, CS y CT en las ratas GB vs Sham, sin diferencias en el PC ni por efecto del polimorfismo de la ECA. La sobreexpresion de ECA2 disminuyó significativamente la RAS (15 por ciento y 27 por ciento), AC (25 por ciento y 25 por ciento ) y PERC (17 por ciento y 18 por ciento) en las ratas LL y BN vs ratas hipertensas, respectivamente. Estos resultados se asociaron a una disminución significativa del CS (LL = 37 por ciento, BN = 39 por ciento), CM (LL = 54 por ciento) y CT (LL = 42 por ciento, BN = 22 por ciento) respecto a las ratas GB. Conclusión: En ratas con HTA...

Objective Background. Over expression of the gene for homologous angiotensin I converting enzyme (ACE) is associated with prevention of angiotensin II dependent cardiac hypertrophy and fibrosis. Whether this over expression is able to reduce hypertension and revert cardiac remodeling is unknown. Aim: To determine whether adenoviral ACE2 gene over expression in the myocardium decreases experimental hypertension and cardiac remodeling in rats with genetically determined levels of ACE and ANGII. Methods: Homozygous normotensive Lewis (LL) and Brown Norway (BN) rats with decreased or increased levéis of ACE and Ang II, respectively, were made hy-pertensive using the Goldblatt procedure. Sham opera-ted rats were used as control s. 5 weeks after surgery, when systolic blood pressure reached > 140 mmHg, rats were randomized to receive intramyocardial injec-tion of either AdACE2 or green fluorescent Ad protein (GFP) as infection controlling agents. One week after adenoviral infection, rats were sacrificed. Body weight (BW, Gr), relative cardiac mass (RCM, mG), systolic blood pressure (SBP, mmHg), cardiomyocite área (MA um2) and perimeter (MPER, uM), and myocardial co-llagen content, both subendocardial (SC, percent) and total (TC percent) were measured. Results: Hypertension was associated to significant in-creases in total and RCM, MA, MPER as well as SC and TC in Goldblatt vs normal rats. This was independent of BW and not affected by ACE polymorphism. ACE II over expression significantly decreased SBP (27 vs 15 percent), MA (25 vs 25 percent) and MPER (18 vs 17 percent) hy-pertensive vs normal rats, respectively. Conclusion: Over expression of ACE2 decreased hypertension, hypertrophy and fibrosis in rats with experimental hypertension and different levels of ACE and Ang II. (Fondecyt 1070662).

Captopril prevents ventricular hypertrophy in sinoaortic denervated rats

We had previously reported that sinoaortic denervation induces cardiac ventricular hypertrophy in rats. The objective of the present study was to determine whether this cardiac hypertrophy can be prevented by inhibition of angiotensin converting enzyme (ACE) with captopril, 20 mg/kg, administered sc twice daily for 15 days. The left ventricular weight/body weight ratio significantly increased (12%) in sinoaortic denervated (SAD) rats 15 days after surgery when compared with the sham-operated group (SO). Administration of captopril to SAD rats prevented this ventricular hypertrophy and decreased but did not completed abolish their high arerial pressure. No changes in the normal pattern of baroreceptor reflex activity were observed in the captopril-pretreated SAD or SO groups. These data suggest the participation of the angiotensin system in the development of cardiac hypertrophy in SAD rats