Diabetes exacerbates myocardial ischemia/reperfusion (IR) injury by incompletely understood mechanisms. We explored whether diabetes diminished BAG3/Bcl-2/Nrf-2/HO-1-mediated cardioprotection and overproduced oxidative stress contributing to exaggerated IR injury. Streptozotocin-induced diabetes enhanced hyperglycemia, cardiac NADPH oxidase p22/p67 expression, malondialdehyde amount and leukocyte infiltration, altered the mesenteric expression of 4-HNE, CaSR, p-eNOS and BAG3 and impaired microvascular reactivity to the vasoconstrictor/vasodilator by a wire myography. In response to myocardial IR, diabetes further depressed BAG3/Bcl-2/Nrf-2/HO-1 expression, increased cleaved-caspase 3/poly(ADP-ribose) polymerase (PARP)/TUNEL-mediated apoptosis and exacerbated IR-induced left ventricular dysfunction characterized by further depressed microcirculation, heart rate, left ventricular systolic pressure and peak rate of pressure increase/decrease (±dp/dt) and elevated left ventricular end-diastolic pressure (LVEDP) and Evans blue-2,3,5-triphenyltetrazolium chloride-stained infarct size in diabetic hearts. Our results implicated diabetes exacerbated IR-induced myocardial dysfunction through downregulated BAG3/Bcl-2/Nrf-2/HO-1 expression, increased p22/p67/caspase 3/PARP/apoptosis-mediated oxidative injury and impaired microvascular reactivity.

Objective Activation of thromboxane A₂ synthase (TXAS)/thromboxane A₂ (TXA₂)/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS^−/−, TP^−/− and TXAS^−/−TP^−/− mice. Approach and Results The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS^−/−, TP^−/− and TXAS^−/−TP^−/− mice in response to intravenous saline, endothelin-1, U46619 (a TXA₂ agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1β, cell apoptosis, coronary effluent thromboxane B₂ (TXB₂) and superoxide anions (O₂ ⁻) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl₃ stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1β, apoptosis, coronary endothelin-1, TXB₂, O₂ ⁻ release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS^−/−, TP^−/− and TXAS^−/−TP^−/− mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl₃ stimulation. Conclusion Inhibiting TXAS/TXA₂/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries. ^* Chih-Yao Chiang and Chen-Yen Chien contributed equally to this study. ^** Po-Yuan Chang and Chiang-Ting Chien contributed equally to this study.

2′-Hydroxycinnamaldehyde (HCA), a natural product isolated from the bark of Cinnamomum cassia, has anti-inflammatory and anti-tumor activities. In this study, we explored whether HCA preconditioning could protect the heart against ischemia/reperfusion (I/R)-induced oxidative injury through cytosolic Bcl-2-associated athanogene 3 (BAG3) upregulation. In vivo HCA preconditioning was performed intraperitoneally in adult male Wistar rats (50 mg/kg body weight) three times/week for 2 weeks before cardiac I/R injury. The animals were divided into sham control (sham), I/R, and HCA preconditioning plus I/R (HCA+I/R) groups. We examined left ventricular pressure cardiac hemodynamics, the microcirculation, electrocardiograms, infarct size, and oxidative stress and performed Western blots, immunohistochemistry, and cytokine array assays. HCA pretreatment, via BAG3 overexpression, inhibited H₂O₂-induced H9c2 cell death. Cardiac I/R injury increased ST-segment elevation, left ventricular end-diastolic pressure, infarct size, myocardial disruption, tissue edema, erythrocyte accumulation, leukocyte infiltration, reactive oxygen species, malondialdehyde, 8-isoprostane, caspase 3-mediated apoptosis, 4HNE/GPX4-mediated ferroptosis, and fibrosis but decreased the microcirculation, cytosolic BAG3, and Beclin-1/LC3 II-mediated autophagy in the I/R hearts. HCA preconditioning significantly decreased these oxidative injuries by increasing cardiac cytosolic BAG3 and Nrf2/HO-1 signaling. HCA preconditioning significantly decreased cardiac I/R-enhanced mitochondrial fission DRP1 expression. Our data suggest that HCA preconditioning can efficiently improve myocardial I/R injury-induced cardiac dysfunction, apoptosis, ferroptosis, mitochondrial fission, and autophagy inhibition through cardiac BAG3 and Nrf2/HO-1 upregulation.

Patient-prosthesis mismatch (PPM) causes a high transvalvular pressure gradient and residual left ventricular (LV) hypertrophy, consequently influencing long-term results. This study aimed to find the relationships between hemodynamic parameters and LV mass regression and determine the risk predictors of major adverse cardiovascular and cerebral events (MACCE) after aortic valve replacement (AVR) for aortic stenosis. Methods and Results: Preoperative and postoperative Doppler echocardiography data were evaluated for 120 patients after AVR. The patients’ mean age was 67.7 years; 55% of the patients were male. Forty-four (37%) patients suffered from MACCE during a mean follow-up period of 3.6 ± 2 years. The following hemodynamic parameters at follow-up were associated with lower relative indexed LV mass (LVMI) regression: lower postoperative indexed effective orifice area, greater mean transvalvular pressure gradient (MPG), greater stroke work loss (SWL), and concentric or eccentric LV remodeling mode. The following hemodynamic parameters at follow-up were associated with a higher risk of MACCE: higher valvuloarterial impedance (Z_VA), greater SWL, greater MPG, greater relative wall thickness, greater LVMI, and hypertrophic LV remodeling mode. Lower relative LVMI regression was associated with a higher risk of MACCE (hazard ratio, 1.01: 95% confidence interval, 1.003–1.03). The corresponding cutoff of relative LVMI regression was −14%. Conclusions: Changes in hemodynamic parameters were independently associated with relative LVMI regression. Impaired reverse remodeling and persistent residual LV hypertrophy were independent risk predictors of MACCE. An LVMI regression lower than 14% indicated higher MACCE. A postoperative Z_VA greater than 3.5 mmHg/mL/m² was an independent risk predictor of cardiac events and mortality after AVR. Preventive strategies should be used at the time of the operation to avoid PPM.

2‘-Hydroxycinnamaldehyde (HCA), a natural product isolated from the bark of Cinnamomum cassia, that has anti-inflammatory and anti-tumor activities. In this study, we explored whether HCA preconditioning could protect heart against ischemia/reperfusion (I/R) induced oxidative injury through cytosolic Bcl-2–associated athanogene 3 (BAG3) upregulation. In vivo HCA preconditioning was performed intraperitoneally 50 mg/kg body weight three times/week for 2 weeks before cardiac I/R injury in adult male Wistar rats. Animals were divided into sham control (SHAM), I/R and HCA preconditioning plus I/R (HCA+I/R) groups. We determined left ventricular pressure cardiac hemodynamics, microcirculation, electrocardiogram, infarct size, oxidative stress, western blot, immunohistochemistry and cytokine array assay. HCA pretreatment through BAG3 overexpression inhibited H2O2 induced H9c2 cell death. Cardiac I/R injury enhanced ST segment elevation, left ventricular end-diastolic pressure, infarct size, myocardial disruption, tissue edema, erythrocyte accumulation, leukocyte infiltration, reactive oxygen species, malondialdehyde, 8-isoprostane, caspase 3 mediated apoptosis, 4HNE/GPX4 mediated ferroptosis and fibrosis but decreased microcirculation, cytosolic BAG3 and Beclin-1/LC3 II mediated autophagy in the I/R hearts. HCA preconditioning significantly depressed these oxidative injury by increased cardiac cytosolic BAG3 and Nrf2/HO-1 signaling. HCA preconditioning significantly decreased cardiac I/R enhanced mitochondrial fission DRP1 expression. Our data suggest HCA preconditioning can efficiently improve myocardial I/R injury evoked cardiac dysfunction, apoptosis, ferroptosis and mitochondrial fission and autophagy inhibition through cardiac BAG3 and Nrf2/HO-1 upregulation.