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Updated: Nov 1, 2025
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Cardiac Tissue Factor Regulates Inflammation, Hypertrophy, and Heart Failure in Mouse Model of Type 1 Diabetes
Dasan Mary Cibi1, Reddemma Sandireddy1, Hanumakumar Bogireddi1
1Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.
Insights
Tissue factor (TF) drives inflammation and cardiac remodeling in diabetes, worsening heart failure with preserved ejection fraction (HFpEF). Reducing TF levels protected against these diabetes-induced heart problems in mice.
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Molecular Biology
Background:
- Diabetes mellitus significantly increases heart failure (HF) risk, particularly HF with preserved ejection fraction (HFpEF).
- The precise mechanisms linking diabetes to HF, especially HFpEF, remain incompletely understood.
- Tissue factor (TF) is implicated in inflammation and atherothrombosis in diabetes, but its cardiac role is unexplored.
Purpose of the Study:
- To investigate the role of Tissue Factor (TF) in the development of type 1 diabetes-induced heart failure (HF).
- To determine if TF mediates cardiac inflammation, hypertrophy, and dysfunction in diabetic conditions.
- To explore the downstream signaling pathways involved in TF's effects on the diabetic heart.
Main Methods:
- Utilized wild-type (WT), heterozygous, and low-TF genetically modified mice to model varying levels of TF.
- Induced type 1 diabetes in mice and assessed cardiac TF expression (mRNA and protein).
- Evaluated cardiac inflammation, hypertrophy, function, and downstream signaling pathways (ERK1/2, STAT3).
Main Results:
- Diabetic WT mice showed significantly increased cardiac TF expression, inflammation, and hypertrophy compared to non-diabetic controls.
- Low-TF mice with diabetes did not exhibit these increases in cardiac inflammation and hypertrophy.
- TF deficiency was linked to improved cardiac function, mitigating HFpEF-like characteristics observed in diabetic WT mice.
- TF's influence on cardiac inflammation and remodeling was dependent on ERK1/2 and STAT3 signaling.
Conclusions:
- Tissue factor plays a critical role in mediating diabetes-induced cardiac inflammation, hypertrophy, and remodeling.
- TF is a key contributor to the development of heart failure with preserved ejection fraction (HFpEF) in the context of diabetes.
- Targeting TF or its downstream pathways may offer therapeutic strategies for diabetic heart disease.
Abstract:
Patients with diabetes have an increased risk of heart failure (HF). Diabetes is highly prevalent in HF with preserved ejection fraction (HFpEF), which is on the rise worldwide. The role of diabetes in HF is less established, and available treatments for HF are not effective in patients with HFpEF. Tissue factor (TF), a transmembrane receptor, plays an important role in immune cell inflammation and atherothrombosis in diabetes. However, its role in diabetes-induced cardiac inflammation, hypertrophy, and HF has not been studied. In this study, we used wild-type (WT), heterozygous, and low-TF (with 1% human TF) mice to determine the role of TF in type 1 diabetes-induced HF. We found significant upregulation of cardiac TF mRNA and protein levels in diabetic WT hearts compared with nondiabetic controls. WT diabetic hearts also exhibited increased inflammation and cardiac hypertrophy versus controls. However, these changes in cardiac inflammation and hypertrophy were not found in low-TF mice with diabetes compared with their nondiabetic controls. TF deficiency was also associated with improved cardiac function parameters suggestive of HFpEF, which was evident in WT mice with diabetes. The TF regulation of inflammation and cardiac remodeling was further dependent on downstream ERK1/2 and STAT3 pathways. In summary, our study demonstrated an important role of TF in regulating diabetes-induced inflammation, hypertrophy, and remodeling of the heart leading to HFpEF.
