Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins

Sanz, Raúl; Inserra, Felipe; Menéndez, Sebastián García; Mazzei, Luciana; Ferder, León; Manucha, Walter

doi:10.1007/s11906-023-01240-w

Cited by 10 publications

(6 citation statements)

References 141 publications

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“…One study has shown that mitochondrial dysfunction oxidative stress affected myocardial and vascular remodeling [ 34 ]. In MetS, mitochondrial oxidative stress is mainly related to excessive reactive oxygen species, mitochondrial-dependent cardiac pump dysfunction, and cardiomyocyte apoptosis, which causes irreversible structural and functional damage to cardiomyocytes, leading to cardiac hypertrophy and remodeling [ 35 , 36 ]. For MetS with OCAD patients, mitochondrial abnormal oxidative stress leads to insufficient myocardial energy supply, which further aggravates myocardial ischemia and hypoxia, leading to myocardial deformation and remodeling.…”

Section: Discussionmentioning

confidence: 99%

The additive effect of metabolic syndrome on left ventricular impairment in patients with obstructive coronary artery disease assessed by 3.0 T cardiac magnetic resonance feature tracking

Min,

Gao,

Jiang

et al. 2024

Cardiovasc Diabetol

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Background Metabolic syndrome (MetS) can increase the risk of morbidity and mortality of cardiovascular disease and obstructive coronary artery disease (OCAD), which usually have a poor prognosis. This study aimed to explore the impact of MetS on left ventricular (LV) deformation and function in OCAD patients and investigate the independent factors of impaired LV function and deformation. Materials and methods A total of 121 patients with OCAD and 52 sex- and age-matched controls who underwent cardiac magnetic resonance scanning were enrolled in the study. All OCAD patients were divided into two groups: OCAD with MetS [OCAD(MetS+), n = 83] and OCAD without MetS [OCAD(MetS−), n = 38]. LV functional and global strain parameters were measured and compared among the three groups. Multivariable linear regression analyses were constructed to investigate the independent factors of LV impairment in OCAD patients. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to test the prediction efficiency of MetS for LV impairment. Results From controls to the OCAD(MetS−) group to the OCAD(MetS+) group, LV mass (LVM) increased, and LV global function index (LVGFI) and LV global longitudinal peak strain (GLPS) decreased (all p < 0.05). Compared with the OCAD(MetS−) group, the LV GLPS declined significantly (p = 0.027), the LVM increased (p = 0.006), and the LVGFI decreased (p = 0.043) in the OCAD(MetS+) group. After adjustment for covariates in OCAD patients, MetS was an independent factor of decreased LV GLPS (β = − 0.211, p = 0.002) and increased LVM (β = 0.221, p = 0.003). The logistic multivariable regression analysis and ROC analysis showed that combined MetS improved the efficiency of predicting LV GLPS reduction (AUC = 0.88) and LVM (AUC = 0.89) increase. Conclusions MetS aggravated the damage of LV deformation and function in OCAD patients and was independently associated with LV deformation and impaired LV strain. Additionally, MetS increased the prediction efficiency of increased LVM and decreased LV GLPS. Early detection and intervention of MetS in patients with OCAD is of great significance.

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Section: Discussionmentioning

confidence: 99%

The additive effect of metabolic syndrome on left ventricular impairment in patients with obstructive coronary artery disease assessed by 3.0 T cardiac magnetic resonance feature tracking

Min,

Gao,

Jiang

et al. 2024

Cardiovasc Diabetol

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“…These drugs have a remarkable effect at the mitochondrial level, in many ways similar to that of CR and complementary to RAS‐blockade. As a result, their potential favorable effect on aging is highly probable (Hoong & Chua, 2021 ; Sanz et al., 2023 ; Scisciola et al., 2023 ). In any case, in order to qualify as candidates for use against human aging, this family of drugs still needs both proof of safety after prolonged use, and cost reduction.…”

Section: Summary and Discussionmentioning

confidence: 99%

Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

de Cavanagh,

Inserra,

Ferder

2024

Physiological Reports

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The renin–angiotensin system (RAS)—a classical blood pressure regulator—largely contributes to healthy organ development and function. Besides, RAS activation promotes age‐related changes and age‐associated diseases, which are attenuated/abolished by RAS‐blockade in several mammalian species. RAS‐blockers also increase rodent lifespan. In previous work, we discussed how RAS‐blockade downregulates mTOR and growth hormone/IGF‐1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D‐receptor upregulation), and proposed that at least some of RAS‐blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS‐blockade's impact on other aging regulatory pathways, that is, TGF‐ß, NF‐kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS‐blockade‐aging regulatory pathway–mitochondria interactions. However, existing results allow to conjecture that RAS‐blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)—even at subclinical doses—offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well‐tolerated anti‐hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement.

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“…Several mechanisms may be involved in improved contractile function [ 17 ]. Studies have shown that SGLT2 inhibitors improve myocardial sodium and calcium homeostasis and energy metabolism, and reduces inflammation, oxidative stress, and myocardial interstitial fibrosis [ 17 , 30 ]. As a probable mechanism, we analyzed the activity of key enzymes in myocardial energy metabolism and myocardial metabolomics.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiovascular outcomes observed in clinical trials were beyond improvement in glycemia [ 8 , 13 – 15 ]. Despite extensive investigation, the mechanisms involved in the clinical benefits have not been completely clarified [ 13 , 15 – 17 ]. As there is concern about SGLT2 inhibition in Type 1 DM individuals, only small studies have addressed its effects in Type 1 DM [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats

Rodrigues,

Rosa,

Campos

et al. 2023

Diabetol Metab Syndr

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Background Sodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established. Objective To evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM. Methods Male Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results DM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM. Conclusion Long-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.

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Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins

Cited by 10 publications

References 141 publications

The additive effect of metabolic syndrome on left ventricular impairment in patients with obstructive coronary artery disease assessed by 3.0 T cardiac magnetic resonance feature tracking

The additive effect of metabolic syndrome on left ventricular impairment in patients with obstructive coronary artery disease assessed by 3.0 T cardiac magnetic resonance feature tracking

Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats

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