Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice

Cozzoli, Anna; Nico, Beatrice; Sblendorio, Valeriana; Capogrosso, Roberta Francesca; Dinardo, Maria Maddalena; Longo, Vito; Gagliardi, S.; Montagnani, Monica; A, De Luca

doi:10.1016/j.phrs.2011.06.002

Cited by 60 publications

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“…At the end of experiments, samples were removed, cleaned from tendons, dried, and weighted. Absolute values of tension were normalized by cross-sectional area as previously described (6,11,14).…”

Section: Methodsmentioning

confidence: 99%

“…In fact gCl reduction in mdx muscles is contrasted by anti-inflammatory agents, while tumor necrosis factor-␣ (TNF-␣), a key modulator of dystrophic muscle necrosis, partially decreases gCl via PKC activation (11,18,21,58). We recently observed that a treatment with enalapril, an inhibitor of the angiotensin-converting enzyme (ACE), while reducing the presence of markers of oxidative stress and inflammation in mdx mouse muscles, also leads to a dose-dependent restoration of gCl (14). This result lead us to hypothesize a possible role of angiotensin II (ANG II) signaling in ClC-1 channel modulation.…”

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confidence: 99%

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Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase

Cozzoli

Liantonio

Conte

et al. 2014

American Journal of Physiology-Cell Physiology

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Cozzoli A, Liantonio A, Conte E, Cannone M, Massari AM, Giustino A, Scaramuzzi A, Pierno S, Mantuano P, Capogrosso RF, Camerino GM, De Luca A. Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT 1 receptor and NADPH oxidase. Am J Physiol Cell Physiol 307: C634 -C647, 2014. First published July 30, 2014; doi:10.1152/ajpcell.00372.2013.-Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC 50 ϭ 0.06 M) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT 1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT 2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT 1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a G q-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers.angiotensin II; chloride channel conductance; AT1 receptor; protein kinase C; NADPH oxidase IN FAST-TWITCH MUSCLE FIBERS, the macroscopic chloride conductance (gCl), due to the expression/activity of ClC-1 channel, accounts for ϳ80% of the total resting ionic conductance and ensures the electrical stability of myofibers (4, 9, 67, 68).In fact, the large gCl prevents membrane overexcitability due to potassium accumulation in transverse tubules during firing by reducing the length constant of electrotonic signal propagation (4, 9, 54). In spite of the important progress made in the last years in measuring ClC-1 chloride currents (25,28,48,60), macroscopic recordings of muscle gCl still provide crucial information about the function, pharmacology, and biochemical modulation of these channels in native skeletal muscle (8,19,20,22...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase

Cozzoli

Liantonio

Conte

et al. 2014

American Journal of Physiology-Cell Physiology

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“…39,40 The maintenance of a constant protocol of exercise and treatment was chosen in order to allow unbiased comparison of drug effects with those obtained in previous trials. 35 Control wild-type animals, age and gender-matched, underwent similar protocols and daily injection of vehicle (sterile water) as needed. Because of the well-described effect of exercise in the mdx phenotype, 36,39 the use of a group of sedentary mdx mice or wild-type exercised mice was not considered informative for the purpose of the present study and was regarded as unethical.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…Every week the animals were monitored for body weight and forelimb force, as described in detail elsewhere. 35 The values at the fourth week were used for statistical analysis. The treatment lasted 4-8 weeks, and the age of the animals at the time of killing was 2-3 months.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…In parallel, PDN improves the histopathological profiles, reducing the markers of oxidative stress and upregulating utrophin, a surrogate of dystrophin. 35,36 This latter effect of PDN likely occurs at translational level. 37 Therefore, the preclinical use of glucocorticoids can be used to determine their mechanisms of action, and can help in the development of strategies to potentiate therapeutic approaches to DMD.…”

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Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Tamma

Annese

Capogrosso

et al. 2013

Laboratory Investigation

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The mdx mouse, the most widely used animal model of Duchenne muscular dystrophy (DMD), develops a seriously impaired blood-brain barrier (BBB). As glucocorticoids are used clinically to delay the progression of DMD, we evaluated the effects of chronic treatment with a-methyl-prednisolone (PDN) on the expression of structural proteins and markers in the brain and skeletal muscle of the mdx mouse. We analyzed the immunocytochemical and biochemical expression of four BBB markers, including endothelial ZO-1 and occludin, desmin in pericytes, and glial fibrillary acidic protein (GFAP) in glial cells, and the expression of the short dystrophin isoform Dp 71, the dystrophin-associated proteins (DAPs), and aquaporin-4 (AQP4) and a-b dystroglycan (DG) in the brain. We evaluated the BBB integrity of mdx and PDN-treated mdx mice by means of intravascular injection of horseradish peroxidase (HRP). The expression of DAPs was also assessed in gastrocnemius muscles and correlated with utrophin expression, and laminin content was measured in the muscle and brain. PDN treatment induced a significant increase in the mRNA and protein content of the BBB markers; a reduction in the phosphorylation of occludin in the brain and of AQP4/b DG in both tissues; an increase of Dp71 protein content; and an increase of both mRNA and protein levels of the AQP4/a-b DG complex. The latter was associated with enhanced laminin and utrophin in the muscle. The HRP assay demonstrated functional restoration of the BBB in the PDN-treated mdx mice. Specifically, mdx mice showed extensive perivascular labeling due to escape of the marker, while HRP was exclusively intravascular in the PDN-treated mice and the controls. These data illustrate for the first time that PDN reverses the BBB alterations in the mdx mouse and re-establishes the proper expression and phosphorylation of b-DG in both the BBB and skeletal muscle. Further, PDN partially protects against muscle damage. The reduction in AQP4 and occludin phosphorylation, coupled with their anchoring to glial and endothelial membranes in PDN-treated mice, suggests that the drug may target the glial and endothelial cells. Our results suggest a novel mechanism for PDN action on cerebral and muscular function, restoring the link between DAPs and the extracellular matrix, most likely through protein kinase inactivation.

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Antihypertensive effect of rapeseed peptides and their potential in improving the effectiveness of captopril

et al. 2020

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BACKGROUND The main objective of this study was to evaluate the safety and antihypertensive activity of rapeseed peptides and to investigate their potential synergy with captopril. RESULTS The peptides were nontoxic with the maximum tolerated dose exceeding 25 g kg−1 BW d−1 for mice and they had angiotensin converting enzyme (ACE) inhibitory activity with IC50 value of 1.27 mg mL−1. Rapeseed peptides did not have a synergistic effect with captopril on inhibiting ACE activity in simulated digestion tests in vitro. But in vivo they could synergistically augment the amplitude range of lowering blood pressure with captopril by approximately 9% and prolong the antihypertensive effect duration time by over 20% in antihypertension tests of spontaneously hypertensive rats. In addition, the inhibiting effect of rapeseed peptides on ACE activity was noticeable in some rat organs in vivo. Nevertheless, when compared to captopril group, the potential synergy of rapeseed peptides with captopril did not cause a further decrease in ACE activity in the organs but their synergy further improved levels of NO (12.7%) and endothelial nitric oxide synthase (74.1%) in rat serum. Further studies of some peptides identified from rapeseed peptides showed that some of the rapeseed peptides (Cys‐Leu, Val‐Ala‐Pro) could markedly increase contents of NO and endothelial nitric oxide synthase. CONCLUSIONS Rapeseed peptides have antihypertensive activity and they showed potential synergy with captopril in antihypertensive performance in vivo. The synergy was not from ACE inhibition but from other pathways, like improvement in endogenous vasodilator contents. © 2020 Society of Chemical Industry

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Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice

Cited by 60 publications

References 44 publications

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Antihypertensive effect of rapeseed peptides and their potential in improving the effectiveness of captopril

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Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice

Cited by 60 publications

References 44 publications

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Antihypertensive effect of rapeseed peptides and their potential in improving the effectiveness of captopril

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Resources

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Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT₁ receptor and NADPH oxidase