Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats

Fiordaliso, Fabio; Bianchi, Roberto; Staszewsky, Lidia; Cuccovillo, Ivan; Doni, Mirko; Laragione, Teresa; Salio, Monica; Savino, Costanza; Melucci, Silvia; Santangelo, Francesco; Scanziani, Eugenio; Masson, Serge; Ghezzi, Pietro; Latini, Roberto

doi:10.1016/j.yjmcc.2004.07.008

Cited by 182 publications

(153 citation statements)

References 45 publications

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“…Diabetes‐induced CM apoptosis has been associated with excessive generation of reactive free radicals even though other inductive pathways exist as well (Dorn, 2009; Robertson et al., 2004). Increased ROS production and reduced antioxidant levels in diabetes have been widely documented in previous reports (Fiordaliso et al., 2004; Houstis et al., 2006). Earlier studies showed that CMs incubated with GLP‐1 or its analogs remained viable and lowered ROS levels and apoptosis rates in both diabetic and nondiabetic models (Inoue et al., 2015; Raab, Vuguin, Stoffers & Simmons, 2009; XiaoTian et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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SummaryLipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon‐like peptide‐1 (GLP‐1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP‐1 analog exendin‐4 and the dipeptidyl peptidase‐4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high‐fat diets were significantly reversed by exendin‐4 and saxagliptin treatments for 8 weeks. We found that exendin‐4 inhibited abnormal activation of the (PPARα)‐CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho‐associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)‐treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin‐4 was abolished by combination therapy with the PPARα agonist wy‐14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin‐4. This conclusion was confirmed in cardiac‐restricted overexpression of PPARα mediated by adeno‐associated virus serotype‐9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP‐1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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“…Previous studies have demonstrated that diabetes causes an increase in cardiac apoptosis [48,49], which may cause loss of contractile myocytes, compensatory hypertrophy, and interstitial fibrosis [50]. This maladaptive cardiac remodeling associated with diabetes increases cardiac muscle stiffness and may contribute to the impaired diastolic function that accompanies diabetic cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy

Hamblin

Friedman

Hill

et al. 2007

Journal of Molecular and Cellular Cardiology

113

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“…In cultured cardiomyocytes, high glucose induces ROS generation and apoptosis (7, 10 -13). In animal models of diabetes, antioxidants attenuate heart failure, suggesting a mechanistic link between hyperglycemia-induced ROS generation, myocyte death, and heart failure (10,14,15). However, antioxidants show limited efficacy in preventing diabetic heart failure in humans, indicating other mechanisms might contribute (16,17).…”

Section: High Glucose Diminishes the Cardiac Transcription/survivalmentioning

confidence: 99%

“…In fact, high concentrations of glucose induce the generation of reactive oxygen species (ROS) 4 and cell death in cultured cardiomyocytes (7, 10 -13). The importance of oxidative stress in diabetic cardiomyopathy is underscored by the ability of various antioxidants to prevent diabetic cardiac damage in animal studies (10,14,15). However, antioxidants are not efficacious in human diabetic cardiomyopathy (16,17), suggesting that mechanisms other than ROS generation might be involved.…”

mentioning

confidence: 99%

Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury

Kobayashi

Mao

Zheng

et al. 2007

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemiainduced cardiac damage remain poorly understood. The transcription factor GATA4 is essential for cardiac homeostasis, and its protein levels are dramatically reduced in the heart in response to diverse pathologic stresses. In this study, we investigated if hyperglycemia affects GATA4 expression in cardiomyocytes and if enhancing GATA4 signaling could attenuate hyperglycemia-induced cardiomyocyte injury. In cultured rat cardiomyocytes, high glucose (HG, 25 or 40 mM) markedly reduced GATA4 protein levels as compared with normal glucose (NG, 5.5 mM). Equal amount of mannitol did not affect GATA4 protein expression (NG, 100 ؎ 12%; mannitol, 97 ؎ 8%, versus HG, 43 ؎ 16%, p < 0.05). The GATA4 mRNA content, either steady-state or polysome-associated, remained unchanged. HG-induced GATA4 reduction was reversed by MG262, a specific proteasome inhibitor. HG did not activate the ubiquitin proteasome system (UPS) in cardiomyocytes as indicated by a UPS reporter, nor did it increase the peptidase activities or protein expression of the proteasomal subunits. However, the mRNA levels of ubiquitin-protein isopeptide ligase (E3) carboxyl terminus of Hsp70-interacting protein (CHIP) were markedly increased in HG-treated cardiomyocytes. CHIP overexpression promoted GATA4 protein degradation, whereas small interfering RNA-mediated CHIP knockdown prevented HG-induced GATA4 depletion. Moreover, overexpression of GATA4 blocked HG-induced cardiomyocyte death. Also, GATA4 protein levels were diminished in the hearts of streptozotocin and db/db diabetic mice (44 ؎ 7% and 67 ؎ 13% of control, p < 0.05), which correlated with increased CHIP mRNA abundance. In summary, increased GATA4 protein degradation may be an important mechanism that contributes to hyperglycemic cardiotoxicity.Diabetes is a major risk factor for the development of various cardiovascular diseases, including atherosclerosis, hypertension, and diabetic cardiomyopathy, which collectively constitute the leading causes of mortality from diabetes. Diabetic cardiomyopathy, independent of vascular pathology, is now recognized as an important causative factor for the heightened risk of heart failure and mortality in diabetic patients (1, 2). The characteristic metabolic abnormalities of diabetes include hyperlipidemia, hyperinsulinemia (type 2 diabetes), and hyperglycemia. The development of diabetic cardiomyopathy correlates with the duration and severity of hyperglycemia. Hyperglycemia induces cardiac damage through a number of biochemical mechanisms, including the formation of advanced glycation end products (3), altered calcium homeostasis (4), enhanced renin-angiotensin system (5), and protein kinase C activation (6). Ultimately, it is thought that hyperglycemia increases oxidative stress inducing cardiomyocyte death leading to heart failure in animals (7, 8) and humans (9) with diabetes. In fact, high concentrations of glucose induce the generation of r...

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Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats

Cited by 182 publications

References 45 publications

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy

Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury

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