Related Experiment Video
Updated: Jun 23, 2026
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
miR-451 Is a Driver of Lipotoxic Injury in Patients with Diabetic Cardiomyopathy
Sarah Costantino1, Shafeeq A Mohammed1, Federico Ranocchi2
1Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Zürich, 8952 Schlieren, Switzerland.
Abstract:
MicroRNA 451 (miR-451) is emerging as a pivotal mediator of cardiac damage in experimental models of diabetic cardiomyopathy. Whether miR-451 plays a detrimental role in the human diabetic myocardium is unknown. The present study investigates miR-451's role in patients with type 2 diabetes (T2D). We show that miR-451 is upregulated in myocardial specimens from T2D patients compared to controls without diabetes and correlates with cardiometabolic parameters, the myocardial triglyceride content and cardiac expression of lipotoxic genes as well as echocardiographic indices of left ventricular dysfunction. Calcium-binding protein 39 (Cab39)-a known target of miR-451 in mouse hearts-was downregulated in T2D patients vs. controls, and its expression negatively correlated with that of miR-451. In cultured human cardiomyocytes (CMs), Ago2 immunoprecipitation confirmed Cab39 to be a direct target of miR-451. Treatment with a high amount of glucose (25mM) and palmitic acid (PA) mimicked miR-451 upregulation and Cab39 downregulation in human CMs. These changes were associated with increased TGs and markers of lipotoxic injury, such as elevated oxidative stress levels, mitochondrial dysfunction and apoptosis. Targeting miR-451 led to restoration of Cab39 levels while rescuing diabetes-induced lipotoxic injury and metabolic dysfunction. By contrast, miR-451 overexpression recapitulated features of lipotoxic damage. Our findings indicate miR-451 to be a potential target for the prevention of myocardial lipotoxic injury in diabetes.
Insights
MicroRNA 451 (miR-451) is elevated in type 2 diabetes (T2D) hearts, causing lipotoxic injury by downregulating Cab39. Targeting miR-451 may prevent diabetic heart damage.
Area of Science:
- Cardiology
- Molecular Biology
- Endocrinology
Background:
- Diabetic cardiomyopathy involves cardiac damage in type 2 diabetes (T2D).
- MicroRNA 451 (miR-451) is implicated in experimental models of cardiac damage.
- The role of miR-451 in human diabetic myocardium remains unclear.
Purpose of the Study:
- To investigate the role of miR-451 in the human myocardium of patients with type 2 diabetes.
- To determine the relationship between miR-451, lipotoxicity, and cardiac dysfunction in T2D.
- To explore miR-451 as a potential therapeutic target for diabetic heart disease.
Main Methods:
- Analysis of myocardial specimens from T2D patients and controls.
- Correlation of miR-451 levels with cardiometabolic parameters and cardiac function.
- Investigation of Calcium-binding protein 39 (Cab39) expression in human cardiomyocytes (CMs).
- In vitro studies using human CMs treated with high glucose and palmitic acid.
- Assessment of lipotoxic injury markers, including oxidative stress, mitochondrial dysfunction, and apoptosis.
- Experimental targeting or overexpression of miR-451 in CMs.
Main Results:
- miR-451 was upregulated in T2D patient hearts and correlated with cardiometabolic parameters and left ventricular dysfunction.
- Calcium-binding protein 39 (Cab39), a direct miR-451 target, was downregulated in T2D hearts.
- High glucose and palmitic acid treatment in human CMs mimicked miR-451 upregulation and Cab39 downregulation.
- These changes were linked to increased triglycerides and lipotoxic injury markers.
- Targeting miR-451 restored Cab39 levels and ameliorated diabetes-induced lipotoxic injury.
- miR-451 overexpression induced lipotoxic damage features.
Conclusions:
- miR-451 plays a detrimental role in the human diabetic myocardium.
- Upregulation of miR-451 contributes to myocardial lipotoxic injury in type 2 diabetes.
- miR-451 is a potential therapeutic target for preventing lipotoxic cardiac damage in diabetes.
Related Concept Videos
01:21Myocarditis I: Introduction
01:27Diabetic Retinopathy