Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging

Ren, Di; Fedorova, Julia; Davitt, Kayla; Le, Tran Ngoc Van; Griffin, John H.; Liaw, Patricia C.; Esmon, Charles T.; Rezaie, Alireza R.; Li, Ji

doi:10.1161/circresaha.121.319044

Cited by 19 publications

(9 citation statements)

References 55 publications

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“…Restore blood supply in time to ischemic myocardium is the most effective treatment for AMI. Reperfusion is a viable therapeutic strategy for ischemic heart disease with high morbidity and mortality ( Ren et al, 2021 ). However, reperfusion may also exacerbate myocardial damage and produce a second blow to the myocardium, such as excessively generating reactive oxygen and nitrogen species ( Daiber et al, 2021 ), increasing release of inflammatory mediators and recruitment of inflammatory cells ( Toldo et al, 2018 ), mitochondrial Ca 2+ overload, and the opening of the mitochondrial permeability transition pore (MPTP) ( Ong et al, 2015 ; Basalay et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics

Li²,

Jin³

et al. 2022

Front. Pharmacol.

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Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia /reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-ɑ, IL-6, and IL-1β, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-a, IL-6, IL-1β, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

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Section: Introductionmentioning

confidence: 99%

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics

Li²,

Jin³

et al. 2022

Front. Pharmacol.

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“…Indeed, given the observed protective effects of cytoprotective APC variants, such as 3K3A-APC, in other pathologies this warrants further investigation. 20 , 42 , 43 , 44 …”

Section: Discussionmentioning

confidence: 99%

Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice

et al. 2023

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The chemotherapeutic drug doxorubicin is cardiotoxic and can cause irreversible heart failure. In addition to being cardiotoxic, doxorubicin also induces activation of coagulation. We determined the effect of thrombin-mediated activation of protease-activated receptor 1 (PAR1) on doxorubicin-induced cardiac injury. Administration of doxorubicin to mice resulted in significantly increased plasma prothrombin fragment 1+2, thrombin-antithrombin complexes and extracellular vesicle tissue factor activity. Importantly, mice expressing low levels of tissue factor, but not factor XII deficient mice, treated with doxorubicin had reduced plasma thrombin-antithrombin complexes compared to controls. To evaluate the role of thrombin mediated activation of PAR1, transgenic mice insensitive to thrombin (Par1R41Q) or to activated protein C (Par1R46Q) were subjected to acute and chronic models of doxorubicin-induced cardiac injury and compared to Par1 wildtype (Par1+/+) and PAR1 deficient (Par1-/-) mice. Critically, Par1R41Q and Par1-/- mice, but not Par1R46Q mice, demonstrated similar reductions in the cardiac injury marker cardiac troponin I, preserved cardiac function and reduced cardiac fibrosis compared to Par1+/+ controls after administration of doxorubicin. Further, inhibition of Gq signaling downstream of PAR1 with the small molecule inhibitor Q94 significantly preserved cardiac function in Par1+/+ but not in Par1R41Q mice subject to the acute model of cardiac injury compared to vehicle controls. In addition, mice with PAR1 deleted in either cardiomyocytes or cardiac fibroblasts demonstrated reduced cardiac injury compared to controls. Taken together, these data suggest that thrombin-mediated activation of PAR1 contributes to doxorubicin induced cardiac injury.

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“…Many obese patients have been shown to develop fibrosis of the myocardium [ 27 , 29 ]. Further, these fibrotic changes have been found to be connected to ventricular stiffness and diastolic dysfunction [ 29 , 30 , 32 ]. Here, we observed that obese mice and humans experienced greater amounts of fibrosis in tissue of the left ventricle compared to their counterparts that were of a more ideal weight or BMI.…”

Section: Discussionmentioning

confidence: 99%

Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

Krause-Hauch

Fedorova

Zoungrana

et al. 2022

Cells

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Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2−/−) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2flox/flox and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients’ LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed.

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Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging

Cited by 19 publications

References 55 publications

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics

Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice

Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

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