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Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2-, and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.

Thrombosis is the common mechanism of various diseases of heart and vasculature and their major morbility and mortality. An efficient, safe and easy thrombolysis method is needed. We tried to develop a new type of ultrasound microbubbles carrying thrombolytics and simultaneously targeting to thrombus, which could bind with thrombus specifically and release the encapsulated drug locally under the ultrasound exposure. Microbubbles carrying tissue plasminogen activator (tPA) and Arg-Gly-Asp-Ser tetrapeptide (RGDS) were prepared by lyopyilization. Their properties were detected, including morphology, particle size, surface potential and pH. The results showed that the microbubbles were suitable for intravenous injection. The envelope rate of tPA, detected by ELISA, was (81.12 +/- 2.44%), and the conjugate rate of RGDS, detected by flow cytometer, was (94.49 +/- 6.19%). The tPA encapsulated in microbubbles kept fibrinolysis activity under the conditions of both natural releasing and ultrasound exposure, checked by agarose fibrin plate process. The contrast-enhanced ultrasonography (CEU) in rabbit liver showed that they were good for enhanced ultrasound imaging. The in vitro thrombolysis of the microbubbles to the blood clots from healthy human was detected with a mimical flowing model propelled by peristaltic pump. The drug-loaded microbubbles plus ultrasound irradiation got higher thrombolysis with the lowest dosage. The tPA-loaded microbubbles targeting to thrombus can be prepared by lyopyilization, which will bring out a novel way for the targeting drug-released thrombolysis therapy.

This study was performed to investigate iron deposition in the brain of type 2 diabetes mellitus (T2DM) patients using quantitative susceptibility mapping (QSM) and the associated cognitive impairments. Sixty patients diagnosed with T2DM were subjected to neuropsychological tests to determine their cognitive status, and the results were used to subdivide the patients into a T2DM without mild cognitive impairment (MCI) group (n = 30) and a T2DM with MCI group (n = 30). All patients underwent high-resolution susceptibility-weighted imaging, and data processing was performed using SMART (Susceptibility Mapping and Phase Artifacts Removal Toolbox) software. The susceptibility values of the bilateral parietal cortex, frontal white matter, caudate nucleus (CN), putamen (PU), globus pallidus, thalamus, red nucleus, substantia nigra (SN), hippocampus (HP) and dentate nucleus were analyzed and correlated with the neuropsychological cognitive scores. Compared with the normal controls (n = 30), the T2DM without MCI group exhibited significantly increased susceptibility values in the left HP, whereas the T2DM with MCI group showed significantly increased susceptibility values in the bilateral CN, HP, left PU and right SN. Compared with the T2DM without MCI group, the T2DM with MCI group exhibited significantly increased susceptibility values in the right CN, SN and left PU. The susceptibility values for the right CN, SN and left PU were closely correlated with neuropsychological cognitive scores. Our results provide a new relation between T2DM and brain iron deposition and suggested that QSM may be a helpful tool in the detection and evaluation of their cognitive impairment in T2DM.

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