Mild Type 2 Diabetes Mellitus Reduces the Susceptibility of the Heart to Ischemia/Reperfusion Injury: Identification of Underlying Gene Expression Changes.

Despite clinical studies indicating that diabetic hearts are more sensitive to ischemia/reperfusion injury, experimental data is contradictory. Although mild diabetes prior to ischemia/reperfusion may induce a myocardial adaptation, further research is still needed. Nondiabetic Wistar (W) and type 2 diabetic Goto-Kakizaki (GK) rats (16-week-old) underwent 45 min occlusion of the left anterior descending coronary artery and 24 h reperfusion. The plasma glucose level was significantly higher in diabetic rats compared to the nondiabetics. Diabetes mellitus was associated with ventricular hypertrophy and increased interstitial fibrosis. Inducing myocardial infarction increased the glucose levels in diabetic compared to nondiabetic rats. Furthermore, the infarct size was smaller in GK rats than in the control group. Systolic and diastolic functions were impaired in W + MI and did not reach statistical significance in GK + MI animals compared to the corresponding controls. Among the 125 genes surveyed, 35 genes showed a significant change in expression in GK + MI compared to W + MI rats. Short-term diabetes promotes compensatory mechanisms that may provide cardioprotection against ischemia/reperfusion injury, at least in part, by increased antioxidants and the upregulation of the prosurvival PI3K/Akt pathway, by the downregulation of apoptotic genes, proinflammatory cytokine TNF-alpha, profibrogenic TGF-beta, and hypertrophic marker alpha-actin-1

Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy

Background: Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the "gold standard" pressure unloading therapy. Methods: Abdominal aortic banding was performed for 6 or 12 weeks. Sham operated animals served as controls. Pressure unloading was induced by removing the aortic constriction after week 6. The animals were treated from week 7 to 12, with 10 mg/kg/day cinaciguat or with placebo p.o., respectively. Cardiac function and morphology were assessed by left ventricular pressure-volume analysis and echocardiography. Additionally, key markers of myocardial hypertrophy, fibrosis, nitro-oxidative stress, apoptosis and cGMP signaling were analyzed. Results: Pressure unloading effectively reversed LVH, decreased collagen accumulation and provided protection against oxidative stress and apoptosis. Regression of LVH was also associated with a full recovery of cardiac function. In contrast, chronic activation of the sGC enzyme by cinaciguat at sustained pressure overload only slightly influenced pre-established hypertrophy. However, it led to increased PKG activity and had a significant impact on interstitial fibrosis, nitro-oxidative stress and apoptosis. Amelioration of the pathological structural alterations prevented the deterioration of LV systolic function (contractility and ejection fraction) and improved myocardial stiffness. Conclusion: Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners

PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells

<p>PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.</p