Search

Maintaining physiological levels of hydrogen sulfide during ischemia is necessary to limit injury to the heart. Because of the anti-inflammatory effects of hydrogen sulfide, we proposed that the hydrogen sulfide donor, sodium sulfide (Na2S), would attenuate myocardial injury through upregulation of protective microRNA-21 (miR-21) and suppression of the inflammasome, a macromolecular structure that amplifies inflammation and mediates further injury.

Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure.

In mouse models of cardiac disease, the type 5 (PDE5)-selective cyclic nucleotide phosphodiesterase inhibitor sildenafil has antihypertrophic and cardioprotective effects attributable to the inhibition of cGMP hydrolysis. To investigate the relevance of these findings to humans, we quantified cGMP-hydrolytic activity and its inhibition by sildenafil in cytosolic and microsomal preparations from the left ventricular myocardium of normal and failing human hearts. The vast majority of cGMP-hydrolytic activity was attributable to PDE1 and PDE3. Sildenafil had no measurable effect on cGMP hydrolysis at 10 nM, at which it is selective for PDE5, but it had a marked effect on cGMP and cAMP hydrolysis at 1 microM, at which it inhibits PDE1. In contrast, in preparations from the left ventricles of normal mice and mice with heart failure resulting from coronary artery ligation, the effects of sildenafil on cGMP hydrolysis were attributable to inhibition of both PDE5 and PDE1; PDE5 comprised approximately 22 and approximately 43% of the cytosolic cGMP-hydrolytic activity in preparations from normal and failing mouse hearts, respectively. These differences in PDE5 activities in human and mouse hearts call into question the extent to which the effects of sildenafil in mouse models are likely to be applicable in humans and raise the possibility of PDE1 as an alternative therapeutic target.

Selective cyclo-oxygenase-2 (COX-2) inhibitors have been shown to preserve hemodynamic performance in experimental models of acute myocardial infarction (AMI) in rodents. The impact of COX-2 inhibition on apoptosis, vascular density, and postinfarction remodeling has not yet been fully characterized. The aim of the present study was to evaluate the effects of parecoxib, a selective COX-2 inhibitor, in an experimental AMI model in the rat.

Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride–stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p < 0.05) and an elevated aortic VTI (145% of baseline, p < 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p < 0.05) and aortic VTI (73% of baseline, p < 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n = 6/group, p < 0.05). The sildenafil-treated group had significant reduction in infarct size (15.5 ± 1.2 versus 33 ± 2.3 in the saline group, % risk area, mean ± SEM, n = 10–15/group, p < 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.

Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan’s blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride–stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p< 0.05) and an elevated aortic VTI (145% of baseline, p< 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p< 0.05) and aortic VTI (73% of baseline, p< 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n6/group, p< 0.05). The sildenafil-treated group had significant reduction in infarct size (15.5 ± 1.2 versus33 ± 2.3 in the saline group, % risk area, mean ± SEM, n10–15/group, p< 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.

C. Kositprapa, R. A. Ockaili and R. C. Kukreja. Bradykinin B2Receptor is Involved in the Late Phase of Preconditioning in Rabbit Heart. Journal of Molecular and Cellular Cardiology(2001) 33, 0000–0000. Activation of bradykinin B2receptor has been shown to confer short-term cardioprotection against a prolonged ischemic insult. The present study was designed to delineate the role of B2receptor in the late phase of ischemic preconditioning. Anesthetized, open chest, male rabbits were assigned to 1 of 6 groups (n=8/group). Ischemic preconditioning was elicited by four 5-min occlusion periods interspersed with 10 min of reperfusion. To test the role of B2receptors, rabbits were pretreated with specific receptor antagonist, HOE-140 (1 μgm/kg IV bolus), 15 min prior to ischemic preconditioning. Additionally, two separate groups of animals were treated by intra-atrial infusion with either bradykinin (0.05 μg/kg/min for 15 min) or saline. Twenty-four hours later, the animals were subjected to 30 min of ischemia and 3 h of reperfusion. Infarct size was determined by tetrazolium staining. Ischemic preconditioning reduced infarct size from 43.09±4.66 to 20.65±1.87 (% risk area, P<0.05), which was blocked by HOE-140 as indicated by increase in infarct size (36.72±4.04%, P<0.05). HOE-140 treatment had no significant effect on infarct size in the sham group. Similarly, intra-atrial infusion of bradykinin caused decrease in the infarct size from 52.36±2.17% in the saline control group to 22.83±1.71% (P<0.05). The degree of infarct limitation with bradykinin was comparable to ischemic preconditioning (20.65±1.87%v22.83±1.71%, P>0.05). For the first time, these results provide evidence for the involvement of B2receptor in the genesis of late phase of ischemic preconditioning.

Activation of bradykinin B₂receptor has been shown to confer short-term cardioprotection against a prolonged ischemic insult. The present study was designed to delineate the role of B₂receptor in the late phase of ischemic preconditioning. Anesthetized, open chest, male rabbits were assigned to 1 of 6 groups (n=8/group). Ischemic preconditioning was elicited by four 5-min occlusion periods interspersed with 10 min of reperfusion. To test the role of B₂receptors, rabbits were pretreated with specific receptor antagonist, HOE-140 (1 μ gm/kg IV bolus), 15 min prior to ischemic preconditioning. Additionally, two separate groups of animals were treated by intra-atrial infusion with either bradykinin (0.05 μ g/kg/min for 15 min) or saline. Twenty-four hours later, the animals were subjected to 30 min of ischemia and 3 h of reperfusion. Infarct size was determined by tetrazolium staining. Ischemic preconditioning reduced infarct size from 43.09±4.66 to 20.65±1.87 (% risk area, P&lt;0.05), which was blocked by HOE-140 as indicated by increase in infarct size (36.72±4.04%, P&lt;0.05). HOE-140 treatment had no significant effect on infarct size in the sham group. Similarly, intra-atrial infusion of bradykinin caused decrease in the infarct size from 52.36±2.17% in the saline control group to 22.83±1.71% (P&lt;0.05). The degree of infarct limitation with bradykinin was comparable to ischemic preconditioning (20.65±1.87%v 22.83±1.71%, P>0.05). For the first time, these results provide evidence for the involvement of B₂receptor in the genesis of late phase of ischemic preconditioning. Copyright 2001 Academic Press

Background:Rapamycin (RAPA, mTOR inhibitor) given at reperfusion protects diabetic rabbit hearts against ischemia/reperfusion (I/R) injury by reducing infarct size and apoptosis. We hypothesized that RAPA administration may preserve post-ischemic cardiac function through decreased inflammation and increased cardiomyocyte proliferation with regulation of YAP- the effector of Hippo pathway).Methods and Results:Diabetes (DM) was induced by administration of alloxan monohydrate (125 mg/kg, i.v.) in New Zealand rabbits (n=12; body weight≈3 kg, 4-month-old). Four weeks after alloxan treatments, conscious diabetic rabbits (maintaining blood glucose>250 mg/dL) were subjected to 45 min of ischemia and 10 days of reperfusion (R) by inflating/deflating previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before onset of R. Post-I/R cardiac function in diabetic rabbit, assessed by echocardiography, showed significant improvement of ejection fraction (EF, Fig. A). Left ventricular fibrosis (Fig. B, evaluated by picrosirius red staining) was attenuated following treatment of RAPA in diabetic rabbits. Immunofluorescence staining revealed the attenuation of post-I/R inflammasome formation with RAPA treatment as shown by reduced ASC aggregation (apoptosis speck-like protein with a caspase recruitment domain) in cardiomyocytes (Fig. C). RAPA suppressed the phosphorylation of YAP in cytosol of cardiomyocytes (Fig. D). Proliferation markers, Ki-67 positive and phospho-Aurora B Kinase positive cells indicated cardiomyocytes were in G2-M phase in RAPA-treated diabetic rabbits after I/R injury (Fig. E).Conclusion:RAPA treatment at reperfusion preserves cardiac function and improves cardiomyocyte proliferation with attenuation of inflammation and possibly regulation of Hippo pathway following I/R injury in diabetes.

We developed a preclinical model of myocardial ischemia/reperfusion (I/R) injury in conscious diabetic rabbits to identify an early pharmacological intervention for patients with diabetes and acute myocardial infarction (AMI). Here, we describe a reproducible protocol for induction of diabetes with subsequent manifestation of myocardial I/R injury in conscious rabbits to mimic the real-life scenario observed in clinical settings. Further, we demonstrate the efficacy of rapamycin at the onset of reperfusion to limit the adverse effect of AMI.

To assess changes in cardiac function in animals with ischemic congestive heart failure (CHF) treated with a selective cyclo-oxygenase-2 (COX-2) inhibitor.

Background:Treatment with rapamycin (RAPA, mTOR inhibitor) protects diabetic (DM) hearts against ischemia/reperfusion (I/R) injury. Coordination between MALAT-1 (Metastasis Associated Lung Adenocarcinoma Transcript 1, a long-noncoding RNA) and microRNA-199 (miR-199) plays an important role in cardiovascular diseases. However, the role of MALAT-1 dependent miR-199 regulation during myocardial infarction (MI) in diabetes is unknown.Methods and Results:Diabetes (blood glucose: 350?24 mg/dL) was induced by administration of alloxan monohydrate (125 mg/kg, i.v.) in New Zealand white rabbits (n=32; average 3kg, 4 month old). Myocardial I/R injury in conscious diabetic rabbit was performed by inflating previously (7 days prior to ischemia) implanted balloon occluder for 45 min. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before onset of reperfusion (3 or 10 days). RAPA treatment at reperfusion preserved post-MI ejection fraction (Fig. A). Post-I/R induction of apoptosis (evaluated by TUNEL staining after 3 days of reperfusion) was attenuated by RAPA treatment in DM hearts (Fig. B). Moreover, treatment with RAPA abolished the suppression of MALAT-1 expression in DM hearts following I/R injury (Fig. C). miRArray chip analysis revealed post-I/R induction of miR-199a-5p, a target of MALAT-1(Fig. D) in DM heart which was suppressed by RAPA (Fig. E). The anti-apoptotic protein Bcl-2, specific target of miR-199a-5p, was significantly down-regulated in heart of DM rabbit following I/R, which was restored upon RAPA treatment (Fig. F).Conclusion:Treatment with RAPA preserves MALAT-1, which potentially acts as sponge to suppress miR-199 and restores the expression of Bcl-2 in the diabetic heart following I/R injury. The MALAT-1-miR-199-Bcl-2 axis is a novel regulatory pathway that plays a critical role in preventing cell death in the diabetic myocardium following treatment with RAPA.