scholarly journals Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy

2022 ◽  
Author(s):  
Carolina Jaquenod De Giusti ◽  
Julieta Palomeque ◽  
Alicia Mattiazzi
Keyword(s):  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy

Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jian Cao ◽  
John A McClung ◽  
Shailendra P Singh ◽  
Lars Bellner ◽  
Maayan Waldman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Control Group ◽  
Protein Markers ◽  
Obesity And Diabetes

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

scholarly journals Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Diabetologia ◽  
2020 ◽  
Vol 63 (5) ◽  
pp. 1072-1087 ◽  
Author(s):  
Bingchao Qi ◽  
Linjie He ◽  
Ya Zhao ◽  
Ling Zhang ◽  
Yuanfang He ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy

scholarly journals Docosahexaenoic acid protects against palmitate-induced mitochondrial dysfunction in diabetic cardiomyopathy

2020 ◽  
Vol 128 ◽  
pp. 110306
Author(s):  
Ting Gui ◽  
Yunlun Li ◽  
Shijun Zhang ◽  
Nan Zhang ◽  
Ying Sun ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: Effect of Mesenchymal Stem Cell with PPAR-γ Agonist or Exendin-4

2017 ◽  
Vol 126 (01) ◽  
pp. 27-38 ◽  
Author(s):  
Mohamed Wassef ◽  
Ola Tork ◽  
Laila Rashed ◽  
Walaa Ibrahim ◽  
Heba Morsi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Diabetic Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Mitochondrial Functions ◽  
Cardioprotective Effects

AbstractTherapy targeting mitochondria may provide novel ways to treat diabetes and its complications. Bone marrow-derived mesenchymal stem cells (MSCs), the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists and exendin-4; an analog of glucagon-like peptide-1 have shown cardioprotective properties in many cardiac injury models. So, we evaluated their effects in diabetic cardiomyopathy (DCM) in relation to mitochondrial dysfunction. This work included seven groups of adult male albino rats: the control group, the non-treated diabetic group, and the treated diabetic groups: one group was treated with MSCs only, the second with pioglitazone only, the third with MSCs and pioglitazone, the forth with exendin-4 only and the fifth with MSCs and exendin-4. All treatments were started after 6 weeks from induction of diabetes and continued for the next 4 weeks. Blood samples were collected for assessment of glucose, insulin, and cardiac enzymes. Hearts were removed and used for isolated heart studies, and gene expression of: myocyte enhancer factor-2 (Mef2), peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC1α), nuclear factor kappa B (NFKB) and autophagic markers: light chain 3 (LC3) and beclin by real-time reverse transcription-polymerase chain reaction. The cardiac mitochondrial protein levels of cardiolipin and uncoupler protein 2 (UCP2) were assessed by ELISA and western blot technique, respectively. Treated groups showed significant improvement in left ventricular function associated with improvement in the cardiac injury and myopathic markers compared to the non treated diabetic group. NFKB was down-regulated while cardiolipin, PGC1α, LC.3 and beclin were up-regulated in all treated groups. These data suggest that the cardioprotective effects of MSCs, exendin-4 or pioglitazone based on their ability to improve mitochondrial functions through targeting inflammatory and autophagy signaling. The co- administration of pioglitazone or exendin-4 with MSCs showed significant superior improvement compared with MSCs alone, indicating the ability to use them in supporting cardioprotective effects of MSCs.

scholarly journals Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction

2020 ◽  
Vol 11 ◽  
Author(s):  
Tingjuan Ni ◽  
Na Lin ◽  
Xingxiao Huang ◽  
Wenqiang Lu ◽  
Zhenzhu Sun ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy

scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

scholarly journals Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Ada Admin ◽  
Adam R. Wende ◽  
John C. Schell ◽  
Chae-Myeong Ha ◽  
Mark E. Pepin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Uptake ◽  
Diabetic Cardiomyopathy ◽  
Transcriptional Repression ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Specific Expression ◽  
Transport Chain ◽  
Atp Generation ◽  
Glucose Transporter Glut4

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

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