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

Abstract

Therapy 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 (), peroxisome proliferator-activated receptor gamma coactivator1-alpha (), nuclear factor kappa B () and autophagic markers: light chain 3 () 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. was down-regulated while cardiolipin,, 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.

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

“…Some studies have attributed the benefits of Ex‐4 on DCM to its effects on infiltrating macrophages, cardiac microvascular injury, and mitochondrial dysfunction (Tate et al., 2016; Wang et al., 2013; Wassef et al., 2017). However, the present study mainly focused on the effects of GLP‐1 on lipid regulation because, along with hyperglycemia, lipid accumulation and toxicity play key roles in DCM (Kusminski et al., 2009; Yang et al., 2007).…”

<i>Astraglaus polysaccharide</i> protects diabetic cardiomyopathy by activating NRG1/ErbB pathway

“…Previous studies showed that, for diabetic cardiomyopathy in hamsters, APS can induce myocardial collagen deposition and improve cardiac function by activating ERK1/2 signal pathway (23,28). Besides, APS can improve cardiac glucose metabolism dysfunction by inducing expression of GLUT-4 and inhibiting PPAR expressing (20,24,29).…”

Bone marrow mesenchymal stem cells inhibit cardiac hypertrophy by enhancing FoxO1 transcription

“…BMSCs are capable of differentiation into cardiomyocytes (Neshati et al, 2018) and releasing cytokines such as vascular endothelial growth factor, basic fibroblast growth factor, and insulin‐like growth factor‐1. To date, preclinical and clinical studies have shown that BMSCs are effective for the treatment of myocardial infarction (Elmadbouh & Ashraf, 2017; Wu et al, 2017; Ju et al, 2018), dilated cardiomyopathy (Mu et al, 2011), and diabetic cardiomyopathy (Wassef et al, 2018) through the promotion of angiogenesis, antiapoptosis, anti‐inflammation, antiremodeling, and antifibrosis, and the activation of resident cardiac stem cells. Previous experiments have shown that BMSCs inhibit pathological myocardial hypertrophy through the Ca 2+ /calcineurin/NFATc3 signaling pathway (Cai et al, 2015).…”