sirolimus and Diabetic-Cardiomyopathies

Mechanistic/Mammalian target of rapamycin (mTOR) orchestrates cellular homeostasis by controlling cell growth, proliferation, metabolism, and survival by integrating various growth factors, nutrients and amino acids. Eccentric synchronization of mTOR has been incriminated in various diseases/disorders like cancer, neurodegenerative disorders, and diabetes mellitus and its complications. Recent reports also highlight the role of mTOR in diabetes and its associated complications. This review tries to fathom the role of mTOR signaling in diabetes mellitus and its complications- diabetic cardiomyopathy, diabetic nephropathy, and diabetic retinopathy and highlights mTOR as a putative target for the development of novel anti-diabetic drug candidates.

Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Diabetic Nephropathies; Humans; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

We performed this meta-analysis to determine which stent among everolimus eluting stents (EES), sirolimus eluting stents (SES) and paclitaxel eluting stents (PES) should be preferred for the treatment of DM patients.. A systematic search of publications about randomized controlled trials (RCTs) focused on diabetic patients received EES, SES or PES was conducted. We evaluated the following indicators: target vessel revascularization (TVR), target lesion revascularization (TLR), late luminal loss (LLL), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality and cardiac mortality.. EES showed obvious advantages over SES for DM patients, as it induced the lowest rate of target vessel revascularization and target lesion revascularization (TLR) (p = 0.04). In addition, EES induced lower in-segment LLL than PSE and SES and lower in-stent LLL than PES in DM patients (all p < 0.05). Moreover, EES effectively reduced all-cause mortality compared to SES (RR = 0.71, 95% CI: 0.52-0.99, p = 0.04) and MI rates compared to PES (RR = 0.44, 95% CI: 0.26-0.73, p = 0.0002). Furthermore, EES could reduce the ST rate compared with both SES (RR = 0.53, 95% CI: 0.28-0.98, p = 0.04) and PES (RR = 0.18, 95% CI: 0.07-0.51, p = 0.001).. Among those three types of stents, EES should be the first recommended stent for DM patients.

Topics: Cardiovascular Agents; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug-Eluting Stents; Everolimus; Humans; Paclitaxel; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Despite the improved clinical outcomes following the availability of second generation drug eluting stents (DES), percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among the patients with diabetes mellitus (DM) than among non-diabetics. The Cre8 Amphilimus-eluting DES is polymer-free, resulting in a reduced inflammatory response and lower risk of stent thrombosis. In a clinical study, it showed equivalent efficacy and safety in diabetic and non-diabetic populations, a unique finding among DES studies. These findings were confirmed in a real-world study, Investig8, and another real-world study, Particip8, is ongoing. The RESERVOIR Clinical Trial recruited patients with DM and showed noninferiority of the Cre8 DES compared to an everolimus eluting DES (EES) in the overall group but showed a statistical superiority of Cre8 in diabetic patients with higher metabolic dysfunctions. The Cre8 DES is therefore a valuable option for this important patient population.

Topics: Clinical Trials as Topic; Diabetic Cardiomyopathies; Drug-Eluting Stents; Echocardiography; Humans; Immunosuppressive Agents; Percutaneous Coronary Intervention; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Studies demonstrated that Ginkgo biloba extract (GBE) played a cardioprotective role in diabetic conditions. Impaired autophagy is one of the mechanisms underlying diabetic cardiomyopathy (DCM). The effect of GBE on autophagy has been observed in several diseases; however, whether GBE can ameliorate DCM by regulating autophagy remains unclear. Here, we investigated the effect of GBE on DCM and the potential mechanisms regarding autophagy using a streptozotocin (STZ)-induced diabetic rat model and a high-glucose (HG)-stimulated H9C2 cell model. We demonstrated that GBE attenuated metabolic disturbances, improved cardiac function, and reduced myocardial pathological changes in diabetic rats. Impaired autophagy as well as dysregulation of the adenosine monophosphate-activated protein kinase/ mammalian target of the rapamycin (AMPK/mTOR) signaling pathway were observed in diabetic hearts, as evidenced by the reduced conversion of LC3B-I to LC3B-II along with excessive p62 accumulation, decreased AMPK phosphorylation, and increased mTOR phosphorylation, which could be reversed by GBE treatment. In vitro, GBE reduced the apoptosis induced by HG in H9C2 cells by activating AMPK and inhibiting mTOR to restore autophagy. However, this effect was inhibited by the AMPK inhibitor Compound C. In conclusion, the ameliorative effect of GBE on DCM might be dependent on the restoration of autophagy through modulation of the AMPK/mTOR pathway.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Mammals; Rats; Sirolimus; TOR Serine-Threonine Kinases

Enhanced mammalian target of rapamycin (mTOR) signalling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischaemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR that has been rationally designed to increase water solubility of rapamycin to facilitate p.o. administration and enhance bioavailability. We examined the effect of Rapatar on the metabolic status and protection against myocardial I/R injury in type 2 diabetic mice.. Adult male db/db mice were treated daily for 10 weeks with Rapatar (0.75 mg·kg. Our studies indicate that chronic treatment with Rapatar improves metabolic status and cardiac function with a reduction of infarct size following myocardial I/R injury in diabetic mice.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Male; Mice; Mice, Obese; Micelles; Myocardial Reperfusion Injury; Nanostructures; Protective Agents; Sirolimus

Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would reduce infarct size in the diabetic hearts through STAT3 signaling. Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of normothermic global ischemia and 60 min of reperfusion in Langendorff mode. Rapamycin (100 nM) was infused at the onset of reperfusion. Myocardial infarct size (IS) was significantly reduced in rapamycin-treated mice (13.3 ± 2.4 %) compared to DMSO vehicle control (35.9 ± 0.9 %) or WT mice (27.7 ± 1.1 %). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in the diabetic heart. To determine the cause and effect relationship of STAT3 in cardioprotection, inducible cardiac-specific STAT3-deficient (MCM TG:STAT3(flox/flox)) and WT mice (MCM TG:STAT3(flox/flox)) were made diabetic by feeding high fat diet (HFD). Rapamycin given at reperfusion reduced IS in WT mice but not in STAT3-deficient mice following I/R. Moreover, cardiomyocytes isolated from HFD-fed WT mice showed resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) when treated with rapamycin during reoxygenation following simulated ischemia. Such protection was absent in cardiomyocytes from HFD-fed STAT3-deficient mice. STAT3 signaling plays critical role in reducing IS and attenuates cardiomyocyte death following reperfusion therapy with rapamycin in diabetic heart.

Topics: Animals; Apoptosis; Blotting, Western; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Reperfusion Injury; Signal Transduction; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases