Targeting Calpain for Heart Failure Therapy

Wang, Yihui; Chen, Biyi; Huang, Chongwen; Guo, Ang; Wu, Jennifer D.; Zhang, Xiaoming; Chen, Rong; Chen, Cheng; Kutschke, William; Weiß, Robert M.; Boudreau, Ryan L.; Margulies, Kenneth B.; Hong, Jiang; Song, Long‐Sheng

doi:10.1016/j.jacbts.2018.05.004

Cited by 49 publications

(24 citation statements)

References 37 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: 89%

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: 89%

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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“…Enhanced proteolytic activity of both calpain and caspase-3 is required for cardiorespiratory muscle dysfunction in a variety of conditions [16,25,26]. Activity of calpain and caspase-3 was measured via western blot analysis of their specific αII-spectrin breakdown products ( Figure 6A and 6B).…”

Section: Differential Expression Of Proteolysis Markers In Cardiac Anmentioning

confidence: 99%

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction. Author contributions AJS, HHS and ARJ designed the study. AJS, BMR, MPW, OK, JY, DDC and DDF performed the experiments and analyzed the data. HHS provided the SS-31. AJS and ARJ wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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“…We and others have provided evidence that ventricular junctophilin-2 expression is decreased in animal models and human heart failure, contributing to excitation-contraction uncoupling through loss of ultrastructural dyadic integrity (17,(37)(38)(39)(40). During increased cardiac stress junctophilin-2 can be proteolytically cleaved by calpain (41,42) or downregulated by miR-24 (38). Remarkably, we found that atrial compared with ventricular junctophilin-2 protein levels in human and mouse hearts were approximately 5-fold lower at baseline and, thus, already below maximally depressed ventricular junctophilin-2 levels found in heart failure or after shRNA-mediated knockdown.…”

Section: Figure 11 Junctophilin-2 Overexpression Attenuates Atrial Lmentioning

confidence: 99%

Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis

et al. 2019

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Targeting Calpain for Heart Failure Therapy

Abstract: Visual Abstract

Cited by 49 publications

References 37 publications

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis

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