A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

Aubdool, Aisah A.; Thakore, Pratish; Argunhan, Fulye; Smillie, Sarah-Jane; Schnelle, Moritz; Srivastava, Salil; Alawi, Khadija M.; Wilde, Elena; Mitchell, Jennifer; Farrell-Dillon, Keith; Richards, Daniel A.; Maltese, Giuseppe; Siow, RC; Nandi, Manasi; Clark, James E.; Shah, Ajay M.; Sams, Anette; Brain, Susan D.

doi:10.1161/circulationaha.117.028388

Cited by 88 publications

(85 citation statements)

References 50 publications

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“…Our results from the in vivo experiments confirmed that chronic (14 days) Ang II exposure resulted in left ventricular hypertrophy (as assessed by WGA and H&E staining) and decreased EF and FS. Aubdool et al (2017) indicated that continuously infused Ang II (1.5 mg·kg −1 ·day −1 ) for 14 days via osmotic mini pumps could induce hypertension, cardiac hypertrophy, and hypertensive HF in mice. In the present study, we did not measure the changes of BP in animals due to our focus on the hypertensive HF.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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“…For instance, in an animal model of Ang II‐induced hypertension, RAMP1 transgenic mice were shown to be protected from increases in their SBP 24 . However, the CGRP and/or CGRP receptor expression profile varies with the state and stage of the disease, including that in the Ang II‐induced model 25,26 . In addition, the change in CGRP receptor expression was suggested to further amplify the responses to CGRP, especially in the hypertension model 27 .…”

Section: Discussionmentioning

confidence: 99%

Calcitonin gene‐related peptide inhibits angiotensin II‐induced NADPH oxidase‐dependent ROS via the Src/STAT3 signalling pathway

Luo

Xian

et al. 2020

J Cellular Molecular Medi

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We had previously demonstrated that the calcitonin gene‐related peptide (CGRP) suppresses the oxidative stress and vascular smooth muscle cell (VSMC) proliferation induced by vascular injury. A recent study also indicated that CGRP protects against the onset and development of angiotensin II (Ang II)‐induced hypertension, vascular hypertrophy and oxidative stress. However, the mechanism behind the effects of CGRP on Ang II‐induced oxidative stress is unclear. CGRP significantly suppressed the level of reactive oxygen species (ROS) generated by NADPH oxidase in Ang II‐induced VSMCs. The Ang II‐stimulated activation of both Src and the downstream transcription factor, STAT3, was abrogated by CGRP. However, the antioxidative effect of CGRP was lost following the expression of constitutively activated Src or STAT3. Pre‐treatment with H‐89 or CGRP8–37 also blocked the CGRP inhibitory effects against Ang II‐induced oxidative stress. Additionally, both in vitro and in vivo analyses show that CGRP treatment inhibited Ang II‐induced VSMC proliferation and hypertrophy, accompanied by a reduction in ROS generation. Collectively, these results demonstrate that CGRP exhibits its antioxidative effect by blocking the Src/STAT3 signalling pathway that is associated with Ang II‐induced VSMC hypertrophy and hyperplasia.

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“…Inflammation and oxidative stress together contribute to cardiac cell dysfunction and apoptosis . Therefore, we have investigated the effects of 6b on cell morphology and apoptosis in hyperglycaemia‐induced in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

An Aza resveratrol–chalcone derivative 6b protects mice against diabetic cardiomyopathy by alleviating inflammation and oxidative stress

You

Qian

Sun

et al. 2018

J Cellular Molecular Medi

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Inflammation and oxidative stress play a crucial role in the development of diabetic cardiomyopathy (DCM). We previously had synthesized an Aza resveratrol–chalcone derivative 6b, of which effectively suppressing lipopolysaccharide (LPS)‐induced inflammatory response in macrophages. This study aimed to investigate the potential protective effect of 6b on DCM and underlying mechanism. In H9c2 myocardial cells, 6b potently decreased high glucose (HG)‐induced cell fibrosis, hypertrophy and apoptosis, alleviating inflammatory response and oxidant stress. In STZ‐induced type 1 diabetic mice (STZ‐DM1), orally administration with 6b for 16 weeks significantly attenuated cardiac hypertrophy, apoptosis and fibrosis. The expression of inflammatory cytokines and oxidative stress biomarkers was also suppressed by 6b distinctly, without affecting blood glucose and body weight. The anti‐inflammatory and antioxidative activities of 6b were mechanistic associated with nuclear factor‐kappa B (NF‐κB) nucleus entry blockage and Nrf2 activation both in vitro and in vivo. The results indicated that 6b can be a promising cardioprotective agent in treatment of DCM via inhibiting inflammation and alleviating oxidative stress. This study also validated the important role of NF‐κB and Nrf2 taken in the pathogenesis of DCM, which could be therapeutic targets for diabetic comorbidities.

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A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

Abstract: Supplemental Digital Content is available in the text.

Cited by 88 publications

References 50 publications

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Calcitonin gene‐related peptide inhibits angiotensin II‐induced NADPH oxidase‐dependent ROS via the Src/STAT3 signalling pathway

An Aza resveratrol–chalcone derivative 6b protects mice against diabetic cardiomyopathy by alleviating inflammation and oxidative stress

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