PB0018 - Activated protein C reduces maladaptive unfolded protein response (UPR) to ameliorate diabetes-accelerated atherosclerosis

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Sameen Fatima, MPhil

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Co-Author(s)

IG

Ihsan Gadi

Scientist
Institute of laboratory medicine, clinical chemistry and molecular diagnostics, Leipzig University
Leipzig, Sachsen, Germany
SA

Saira Ambreen

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
KS

Kunal Singh

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
AG

Anubhuti Gupta

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Ahmed Elwakiel, M.Sc.

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany.
Leipzig, Sachsen, Germany
SK

Shruthi Krishnan

Post Doctoral researcher
University of Leipzig
Leipzig, Sachsen, Germany
AM

Akash Methew

PhD Researcher
Institute of laboratory medicine and molecular diagnostics University Hospital Leipzig Germany.
Leipzig, Sachsen-Anhalt, Germany
HK

Hamzah Khawaja

PhD Researcher
Institute of laboratory medicine and molecular diagnostics University Hospital Leipzig Germany.
Leipzig, Sachsen, Germany
SK

Shrey Kohli, PhD

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Berend Isermann, PhD MD

Institute director
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Khurrum Shahzad

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Background: The mechanisms underlying the different atherosclerosis course in diabetic and non-diabetic patients remain unknown. Hyperglycemia causes endothelial cells dysfunction, a key disease driver. Atherosclerotic plaques display markers of senescence and unfolded protein response (UPR). Plasma levels of coagulation protease, activated protein C decline in diabetes and atherosclerosis.

Aims: Our aim is to study the role activated protein C which is well known for its cytoprotective and anti-inflamamtory functions. We hypothesized that activated protein C prevents diabetes induced accelerated atherosclerosis by reducing maladaptive UPR induced endothelial cell senescence.

Methods: To gain insights into pathomechanisms of diabetes induced atherosclerotic plaque development we cultured human coronary artery endothelial cells (HCAECs) under hyperglycemic (HG) or hyperlipidaemic (HL) conditions. ApoE-/- mice (age 8 weeks) was made either diabetic by streptozotocin injections (A mouse model type 1 diabetes) or fed them HFD to induce hyperlipidemia. Mice were analyzed after 20 weeks of treatments.

Results: HG conditions induced strong barrier disruption as compared to HL (TEER, FITC dextran leakage) and protein expression of the senescence markers (p21, p16, p53) and UPR markers (XBP1, IRE1α and ATF6). Activated protein C restored barrier integrity, reduced glucose induced expression of senescence and UPR markers in vitro. Targeting IRE1α RNAase activity prevented HG induced cellular senescence. Ex vivo, diabetic ApoE-/- mice revealed increased expression of senescence, inflammation and UPR markers within atherosclerotic lesion as compared with non-diabetic ApoE-/- mice.

Conclusion(s): Senescence associated inflammation and UPR are associated with glucose-dependent endothelial cells dysfunction and loss of endothelial barrier integrity. These results demonstrate that diabetes-induced atherosclerosis is associated with cellular senescence and UPR. Targeting cellular senescence and UPR (with aPC or IRE1α inhibitor) may be a useful therapy of atherosclerosis in diabetic patients.