Cardiac-specific overexpression of insulin-like growth factor II receptor-α interferes with the regulation of calcium homeostasis in the heart under hyperglycemic conditions.

BACKGROUND: Diabetic cardiomyopathy is a progressive disease caused by inexplicit mechanisms, and a novel factor, insulin-like growth factor II receptor-α (IGF-IIRα), may contribute to aggravating its pathogenesis. We hypothesized that IGF-IIRα could intensify diabetic heart injury. METHODS AND RESULTS: To demonstrate the potential role of IGF-IIRα in the diabetic heart, we used (SD-TG [IGF-IIRα]) transgenic rat model with cardiac-specific overexpression of IGF-IIRα, along with H9c2 cells, to study the effects of IGF-IIRα in the heart under hyperglycemic conditions. IGF-IIRα was found to remodel calcium homeostasis and intracellular Ca2+ overload-induced autophagy disturbance in the heart during diabetes. IGF-IIRα overexpression induced intracellular Ca2+ alteration by downregulating phosphorylated phospholamban/sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (PLB/SERCA2a), resulting in the suppression of Ca2+ uptake into the endoplasmic reticulum. Additionally, IGF-IIRα itself contributed to Ca2+ withdrawal from the endoplasmic reticulum by increasing the expression of CaMKIIδ in the active form. Furthermore, alterations in Ca2+ homeostasis significantly dysregulated autophagy in the heart during diabetes. CONCLUSIONS: Our study reveals the novel role of IGF-IIRα in regulating cardiac intracellular Ca2+ homeostasis and its related autophagy interference, which contribute to the development of diabetic cardiomyopathy. In future, the present study findings have implications in the development of appropriate therapy to reduce diabetic cardiomyopathy.

A combination of isoliquiritigenin with Artemisia argyi and Ohwia caudata water extracts attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/Ho-1 signaling pathways in SD rats with doxorubicin-induced acute cardiotoxicity.

Ohwia caudata (Thunb.) H. Ohashi (Leguminosae) also called as "Evergreen shrub" and Artemisia argyi H.Lév. and Vaniot (Compositae) also named as "Chinese mugwort" those two-leaf extracts frequently used as herbal medicine, especially in south east Asia and eastern Asia. Anthracyclines such as doxorubicin (DOX) are commonly used as effective chemotherapeutic drugs in anticancer therapy around the world. However, chemotherapy-induced cardiotoxicity, dilated cardiomyopathy, and congestive heart failure are seen in patients who receive DOX therapy, with the mechanisms underlying DOX-induced cardiac toxicity remaining unclear. Mitochondrial dysfunction, oxidative stress, inflammatory response, and cardiomyocytes have been shown to play crucial roles in DOX-induced cardiotoxicity. Isoliquiritigenin (ISL, 10 mg/kg) is a bioactive flavonoid compound with protective effects against inflammation, neurodegeneration, cancer, and diabetes. Here, in this study, our aim is to find out the Artemisia argyi (AA) and Ohwia caudata (OC) leaf extract combination with Isoliquiritigenin in potentiating and complementing effect against chemo drug side effect to ameliorate cardiac damage and improve the cardiac function. In this study, we showed that a combination of low (AA 300 mg/kg; OC 100 mg/kg) and high-dose(AA 600 mg/kg; OC 300 mg/kg) AA and OC water extract with ISL activated the cell survival-related AKT/PI3K signaling pathway in DOX-treated cardiac tissue leading to the upregulation of the antioxidant markers SOD, HO-1, and Keap-1 and regulated mitochondrial dysfunction through the Nrf2 signaling pathway. Moreover, the water extract of AA and OC with ISL inhibited the inflammatory response genes IL-6 and IL-1ß, possibly through the NFκB/AKT/PI3K/p38α/NRLP3 signaling pathways. The water extract of AA and OC with ISL could be a potential herbal drug treatment for cardiac hypertrophy, inflammatory disease, and apoptosis, which can lead to sudden heart failure.

Insulin-like growth factor II receptor alpha overexpression in heart aggravates hyperglycemia-induced cardiac inflammation and myocardial necrosis.

Diabetes-induced cardiovascular complications are mainly associated with high morbidity and mortality in patients with diabetes. Insulin-like growth factor II receptor α (IGF-IIRα) is a cardiac risk factor. In this study, we hypothesized IGF-IIRα could also deteriorate diabetic heart injury. The results presented that both in vivo transgenic Sprague-Dawley rat model with specific IGF-IIRα overexpression in the heart and in vitro myocardium H9c2 cells were used to investigate the negative function of IGF-IIRα in diabetic hearts. The results showed that IGF-IIRα overexpression aided hyperglycemia in creating more myocardial injury. Pro-inflammatory factors, such as Tumor necrosis factor-alpha, Interleukin-6, Cyclooxygenase-2, Inducible nitric oxide synthase, and Nuclear factor-kappaB inflammatory cascade, are enhanced in the diabetic myocardium with cardiac-specific IGF-IIRα overexpression. Correspondingly, IGF-IIRα overexpression in the diabetic myocardium also reduced the PI3K-AKT survival axis and activated mitochondrial-dependent apoptosis. Finally, both ejection fraction and fractional shortening were be significantly decrease in diabetic rats with cardiac-specific IGF-IIRα overexpression. Overall, all results provid clear evidence that IGF-IIRα can enhance cardiac damage and is a harmful factor to the heart under high-blood glucose conditions. However, the pathophysiology of IGF-IIRα under different stresses and its downstream regulation in the heart still require further research.

Isoliquiritigenin ameliorates advanced glycation end-products toxicity on renal proximal tubular epithelial cells.

Diabetic nephropathy is a serious chronic complication affecting at least 25% of diabetic patients. Hyperglycemia associated advanced glycation end-products (AGEs) increase tubular epithelial-myofibroblast transdifferentiation (TEMT) and extracellular matrix synthesis and thereby causes renal fibrosis. The chalcone isoliquiritigenin, found in many herbs of Glycyrrhiza family, is known for potential health-promoting effects. However, their effects on AGE-associated renal proximal tubular fibrosis are not known yet. In this study, the effect of isoliquiritigenin on AGE-induced renal proximal tubular fibrosis was determined in cultured HK-2 cell line. The results show that 200 µg/mL of AGE-induced TEMT and the formed myofibroblasts synthesized collagen to increase extracellular matrix formation thereby lead to renal tubular fibrosis. However, treatment with 200 nM of isoliquiritigenin considerably inhibited the TEMT and suppressed the TGFß/STAT3 mechanism to inhibit collagen secretion. Therefore, isoliquiritigenin effectively suppressed AGE-induced renal tubular fibrosis.

Bioactive dipeptide from potato protein hydrolysate combined with swimming exercise prevents high fat diet induced hepatocyte apoptosis by activating PI3K/Akt in SAMP8 mouse.

Obesity in aged population have surges the occurrence of various metabolic disorders including Nonalcoholic fatty liver disease (NAFLD). Apoptosis in the liver is one of the causative factors for NAFLD-induced liver damage. Plants derived bioactive peptides have been shown as an alternative treatment approach for the treating NAFLD due to its less toxicity. Moderate exercise has been reported to improve cellular physiological function prevent age associated metabolic disorders. In the present study, we evaluate the effects of bioactive dipeptide (IF) derived from alcalase potato-protein hydrolysates and swimming exercise in preventing High Fat Diet (HFD)-induced liver damage in senescence accelerated mouse-prone 8 (SAMP8) mice model. Mouse were fed with HFD for 6 weeks followed by oral IF administration or swimming exercise and both for 8 weeks. HFD induces significant structural changes in liver of HFD fed SAMP8 mouse. Both IF administration and exercise prevent the structural abnormalities induced by HFD, however, combined IF treatment and exercise offer better protection. Combined IF treatment and exercise activate PI3K/Akt cell survival protein and effectively inhibit Fas-FADD-induced apoptosis in HFD fed aged mouse. Oral supplementation of bioactive peptide IF combined with moderate swimming exercise effectively alleviate HFD-induced hepatic injury in aged mice.

Inhibition of cell death-inducing p53 target 1 through miR-210-3p overexpression attenuates reactive oxygen species and apoptosis in rat adipose-derived stem cells challenged with Angiotensin II.

Hypoxic preconditioning is a well-known strategy to improve the survival and therapeutic potential of stem cells against various challenges including hemodynamic and neurohormonal modulations. However, the mechanism involved in hypoxia-induced benefits on stem cells is still ambiguous. In pathological hypertension, the elevation of the neurohormonal mediator Angiotensin II (Ang II) causes the adverse effects to stem cells. In this study, we investigate the effect and mechanism of action of short term hypoxia-inducible miRNA in suppressing the effects of AngII on stem cells. According to the results obtained, Ang II affects the normal cell cycle and triggers apoptosis in rADSCs with a corresponding increase in the expression of cell death-inducing p53 target 1 (CDIP1) protein. However, the short term hypoxia-inducible miRNA-miR-210-3p was found to target CDIP1 and reduce their levels upon the Ang II challenge. CDIP1 induces stress-mediated apoptosis involving the extrinsic apoptosis pathway via Bid/Bax/cleaved caspase3 activation. Administration of mimic miR-210-3p targets CDIP1 mRNA by binding to the 3' UTR region as confirmed by dual luciferase assay and also reduced Ang II-induced mitochondrial ROS accumulation as analyzed by MitoSOX staining. Moreover, the present study demonstrates the mechanism of miR-210-3p in the regulation of Ang II-induced CDIP1-associated apoptotic pathway in rADSCs.

ß-catenin/LEF1/IGF-IIR Signaling Axis Galvanizes the Angiotensin-II- induced Cardiac Hypertrophy.

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of ß-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/ß-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition ß-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by ß-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of ß-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.

Anti-apoptotic effects of diosgenin on ovariectomized hearts.

BACKGROUND: The anti-apoptotic effects of diosgenin, a steroid saponin, on hearts in female with estrogen deficiency have been less studied. This study aimed to evaluate the anti-apoptotic effects of diosgenin on cardiac widely dispersed apoptosis in a bilateral ovariectomized animal model. METHODS: A total of 60 female Wistar rats, aged 6-7 months, were divided into the sham-operated group (Sham), bilateral ovariectomized rats for 2 months, and ovariectomized rats administered with 0, 10, 50, or 100 mg/kg diosgenin daily (OVX, OVX 10, OVX 50, and OVX 100, respectively) in the second month. The excised hearts were analyzed by H&E staining, TUNEL(+) assays and Western Blot. RESULT: Cardiac TUNEL(+) apoptotic cells, the levels of Fas ligand, Fas death receptors, Fas-associated death domain, active caspase-8, and active caspase-3 (FasL/Fas-mediated pathways) as well as the levels of Bax, Bad, Bax/Bcl2, Bad/p-Bad, cytosolic Cytochrome c, active caspase-9, and active caspase-3 (mitochondria-initiated pathway) were increased in OVX compared with Sham group but those were decreased in OVX 50 compared with OVX. CONCLUSION: Diosgenin appeared to prevent or suppress ovariectomy-induced cardiac FasL/Fas-mediated and mitochondria-initiated apoptosis. These findings might provide one of the possible therapeutic approaches of diosgenin for potentially preventing cardiac apoptosis in women after bilateral ovariectomy or women with estrogen deficiency.

Involved intrinsic apoptotic pathway in the varicocele and varicose veins.

BACKGROUND: Disordered programmed cell death may play a role in the development of venous diseases. Tissue hypoxia caused by blood stagnation and venous hypertension is the similar etiology of varicocele and varicose veins. We studied the vascular histopathology and determined whether there is the same apoptotic pathway in both venous diseases. METHODS: The study groups consisted of 1-cm venous segments obtained from 10 patients during vascular stripping surgery for varicose saphenous vein and 1 cm of internal spermatic veins obtained from 12 patients during left varicocele repair. The control samples of 1 cm internal spermatic vein were obtained from 10 male patients who underwent left inguinal herniorrhaphy. The three layers of vascular histology were measured and compared by Masson trichrome stain, and the apoptotic proteins including Bcl-2, Fas, cleaved caspase-9, cleaved caspase-8, and cleaved caspase-3 were detected. Data were analyzed using the one-way analysis of variance with Tukey's comparison test. RESULTS: The relative thickness of intima and adventitia layer was smaller in both study groups than in the control group. But a significant hypertrophy of media layer was observed in the varicocele and varicose veins than in the control group (p < 0.05). Overexpression of Bcl-2 and decreased expressions of cleaved caspase-9 and cleaved caspase-3 was observed in both study groups. There is no statistical difference in Fas and cleaved caspase-8 expressions in the control and study groups. CONCLUSION: Our data showed vascular smooth muscle hypertrophy in the diseased vessels. The same dysregulation of apoptosis through intrinsic pathway was demonstrated in varicocele and varicose veins under tissues hypoxia. This mechanism of reduced apoptosis might contribute to the dilated and thickened walls of both venous diseases.

Human electronegative low-density lipoprotein modulates cardiac repolarization via LOX-1-mediated alteration of sarcolemmal ion channels.

Dyslipidemia is associated with greater risk of ventricular tachyarrhythmias in patients with cardiovascular diseases. We aimed to examine whether the most electronegative subfraction of low-density lipoprotein (LDL), L5, is correlated with QTc prolongation in patients with coronary artery disease (CAD) and investigate the effects of human L5 on the electrophysiological properties of cardiomyocytes in relation to the lectin-like oxidized LDL receptor (LOX-1). L5 was isolated from the plasma of 40 patients with angiography documented CAD and 13 patients with no CAD to correlate the QTc interval respectively. The mean concentration of L5 was higher and correlated with QTc in patients with CAD compared to controls. To examine the direct effect of L5 on QTc, mice were intravenously injected with L5 or L1. L5-injected wild-type but not LOX-1-/- mice showed longer QTc compared to L1-injected animals in vivo with corresponding longer action potential duration (APD) in cardiomyocytes incubated with L5 in vitro. The APD prolongation was mediated by an increase of L-type calcium current and a decrease of transient outward potassium current. We show that L5 was positively correlated with QTc prolongation in patients with ischemic heart disease. L5 can modulate cardiac repolarization via LOX-1-mediated alteration sarcolemmal ionic currents.