Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice

Tsuruda, Toshihiro; Sekita-Hatakeyama, Yoko; Hao, Yilin; Sakamoto, Sumiharu; Kurogi, Syuji; Nakamura, Midori; Udagawa, Nobuyuki; Funamoto, Taro; Sekimoto, Tomohisa; Hatakeyama, Kinta; Chosa, Etsuo; Kato, Jun; Asada, Yujiro; Kïtamura, Kazuo

doi:10.1161/hypertensionaha.115.06689

Cited by 20 publications

(17 citation statements)

References 40 publications

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“…Cardiac hypertrophy and pulmonary oedema are serious complications that often occur in the final stages of HF (Delafontaine & Akao, 2006;von Haehling, Ebner, Dos Santos, Springer, & Anker, 2017). To observe the progression of Ang IIinduced HF, rat heart/body weight ratios (Figure 2g) and lung/body weight ratios (Figure 2h) and gastrocnemius muscle weight/body weight ratio (Figure 2i) were determined at the end of the experiment, as in earlier studies (Tsuruda et al, 2016;Wang, Chen, et al, 2018;Wang, Fernandez-Sanz, & Sheu, 2018). Our data showed that Ang II-induced marked rat body weight loss (cachexia) and pulmonary oedema, which was not observed in the Ang II + SIM group.…”

Section: Simvastatin Improves Cardiac Function In Ang Ii-induced Hfmentioning

confidence: 91%

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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Background and PurposeMitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.Experimental ApproachRats were treated with angiotensin II (1.5 mg·kg−1·day−1) or co‐administered simvastatin (oral, 10 mg·kg−1) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨ m) changes were measured by flow cytometry and JC‐1 staining, respectively. Autophagy and mitophagy‐related and mitochondria‐regulated apoptotic proteins were identified by immunohistochemistry and western blotting.Key ResultsSimvastatin significantly reduced ROS production and attenuated the disruption of ΔΨ m. Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria‐mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis.Conclusion and ImplicationsMitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

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Section: Simvastatin Improves Cardiac Function In Ang Ii-induced Hfmentioning

confidence: 91%

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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“…Interestingly, we also found that patients who were on higher doses of renin-angiotensin-system (RAS) blockers had lower OPG levels. This is indirectly supported by Tsuruda et al who demonstrated that OPG levels increase in response to cardiac damage during angiotensin II-induced hypertrophy in mice [45]. Therefore, the question is raised whether serial assessment of circulating OPG may be used to identify patients who respond poorly to RAS inhibition.…”

Section: Discussionmentioning

confidence: 93%

Utility of temporal profiles of new cardio-renal and pulmonary candidate biomarkers in chronic heart failure

Branković

Akkerhuis

Mouthaan

et al. 2019

International Journal of Cardiology

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“…ANG II-induced upregulation of osteoprotegerin by cardiac cells, including infiltrating macrophages, was found to protect against the development of eccentric hypertrophy and dilated cardiomyopathy by enhancing collagen synthesis and inhibiting cardiac myocyte apoptosis. Osteoprotegerin is a secretory glycoprotein belonging to the TNF receptor superfamily that generally acts as a decoy receptor for RANKL, but that was not so in this case (1070). Although not well studied, the engagement of adaptive immunity by ANG II may also impact on cardiac hypertrophy and overall structural remodeling of the heart.…”

Section: Ang II In Cardiac Hypertrophymentioning

confidence: 88%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

773

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice

Abstract: SummaryOsteoprotegerin plays a critical role in angiotensin II-induced cardiac remodeling, and lack of this gene leads to dilate left ventricular chamber, resulting in functional left ventricular decompensation.

Cited by 20 publications

References 40 publications

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Utility of temporal profiles of new cardio-renal and pulmonary candidate biomarkers in chronic heart failure

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

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