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Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice.

ABSTRACT: BACKGROUND:Transforming growth factor beta (TGF-?)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-?-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. METHODS:Male C57BL/6?J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20?mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14?days postsurgery. RESULTS:Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14?days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14?days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-? and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14?days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. CONCLUSIONS:ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.

SUBMITTER: Kakutani N

PROVIDER: S-EPMC7183133 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice.

Kakutani Naoya N Takada Shingo S Nambu Hideo H Matsumoto Junichi J Furihata Takaaki T Yokota Takashi T Fukushima Arata A Kinugawa Shintaro S

Skeletal muscle 20200425 1

<h4>Background</h4>Transforming growth factor beta (TGF-β)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-β-Smad2/3 signaling, is increased in mice w ...[more]

PMID: 32334642

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Project description:PurposeMyocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI.MethodsC57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology.ResultsMyocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation.ConclusionsWhole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

Project description:BackgroundSkeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD.MethodsThis double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes.ResultsEighty patients were enrolled (mean [SD], 65 [8] years, FEV1 43% [21%] predicted, 53% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (?-10.5 mm Hg; 95% CI, -19.9 to -1.1; P = .03) and serum ACE activity (?-20.4 IU/L; 95% CI, -31.0 to -9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (?0.5 s; 95% CI, -13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (?-0.03 arbitrary units; 95% CI, -0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: ?1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: ?3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51).ConclusionsThis randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness.Trial registryCurrent Controlled Trials; No.: ISRCTN05581879; URL: www.controlled-trials.com.

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Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice.

Publications

Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice.

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