Abstract/Description
Mitochondria Targeted Dicarbonyl Scavenging with Mito2HOBA Reduces Atherosclerosis by Enhancing Plaque Stability and Suppressing Inflammation in Hyperlipidemic Ldlr⁻/⁻ Mice
Michael DiLeonardo1, Huan Tao PhD2, Lei Ding BS2, Youmin Zhang BS2, Sergey Dikalov PhD3, Patricia G. Yancey PhD2, and MacRae F. Linton MD2
1Eastern Virginia Medical School, Department of Medicine 2Cardiovascular Medicine and 3Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
Introduction: Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation, immune cell activation, and oxidative stress. Recent evidence indicates that macrophage mitochondrial dysfunction contributes to the development and progression of atherosclerosis. This dysfunction leads to increased reactive oxygen species (ROS) production, promoting immune cell recruitment, inflammation, and, ultimately, the formation and disruption of atherosclerotic plaques. Mito2HOBA is a mitochondrial targeted scavenger of reactive dicarbonyls that has been shown to reduce inflammation. We hypothesized that Mito2HOBA treatment would reduce atherogenesis and promote plaque stability in hyperlipidemic Ldlr⁻/⁻ mice.
Methods: Ldlr⁻/⁻ mice were fed a Western diet to induce atherosclerosis and were treated with either Mito2HOBA or vehicle (water) control during the lesion development and progression phase. Various assays and evaluative methods were then used to determine the effect of Mito2HOBA on atherogenesis, plaque stability, and mitochondrial inflammation and function.
Results: Mito2HOBA treatment significantly reduced atherosclerotic lesion area without impacting serum cholesterol or triglyceride levels compared to the controls. In addition, Mito2HOBA treatment reduced necrotic core area, and increased collagen deposition, indicating improved plaque stability. Moreover, Mito2HOBA treatment inhibited oxidized lipid (OX-PC, MDA and 4-HNE) formation in both mice and macrophages, and preserved macrophage mitochondria integrity and functions, decreasing macrophage pro-inflammatory cytokine (IL-1β and TNF-α) formation.
Conclusion: Mito2HOBA inhibits atherogenesis and enhances plaque stability by reducing macrophage driven inflammation and preserving mitochondrial integrity. These findings support the therapeutic potential of Mito2HOBA in preventing the development and progression of atherosclerosis and promoting plaque stabilization.
Faculty Advisor/Mentor
MacRae Linton
Faculty Advisor/Mentor Email
macrae.linton@vumc.org
Faculty Advisor/Mentor Department
Vanderbilt Department of Cardiovascular Medicine
Mitochondria Targeted Dicarbonyl Scavenging with Mito2HOBA Reduces Atherosclerosis by Enhancing Plaque Stability and Suppressing Inflammation in Hyperlipidemic Ldlr⁻/⁻ Mice
Mitochondria Targeted Dicarbonyl Scavenging with Mito2HOBA Reduces Atherosclerosis by Enhancing Plaque Stability and Suppressing Inflammation in Hyperlipidemic Ldlr⁻/⁻ Mice
Michael DiLeonardo1, Huan Tao PhD2, Lei Ding BS2, Youmin Zhang BS2, Sergey Dikalov PhD3, Patricia G. Yancey PhD2, and MacRae F. Linton MD2
1Eastern Virginia Medical School, Department of Medicine 2Cardiovascular Medicine and 3Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
Introduction: Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation, immune cell activation, and oxidative stress. Recent evidence indicates that macrophage mitochondrial dysfunction contributes to the development and progression of atherosclerosis. This dysfunction leads to increased reactive oxygen species (ROS) production, promoting immune cell recruitment, inflammation, and, ultimately, the formation and disruption of atherosclerotic plaques. Mito2HOBA is a mitochondrial targeted scavenger of reactive dicarbonyls that has been shown to reduce inflammation. We hypothesized that Mito2HOBA treatment would reduce atherogenesis and promote plaque stability in hyperlipidemic Ldlr⁻/⁻ mice.
Methods: Ldlr⁻/⁻ mice were fed a Western diet to induce atherosclerosis and were treated with either Mito2HOBA or vehicle (water) control during the lesion development and progression phase. Various assays and evaluative methods were then used to determine the effect of Mito2HOBA on atherogenesis, plaque stability, and mitochondrial inflammation and function.
Results: Mito2HOBA treatment significantly reduced atherosclerotic lesion area without impacting serum cholesterol or triglyceride levels compared to the controls. In addition, Mito2HOBA treatment reduced necrotic core area, and increased collagen deposition, indicating improved plaque stability. Moreover, Mito2HOBA treatment inhibited oxidized lipid (OX-PC, MDA and 4-HNE) formation in both mice and macrophages, and preserved macrophage mitochondria integrity and functions, decreasing macrophage pro-inflammatory cytokine (IL-1β and TNF-α) formation.
Conclusion: Mito2HOBA inhibits atherogenesis and enhances plaque stability by reducing macrophage driven inflammation and preserving mitochondrial integrity. These findings support the therapeutic potential of Mito2HOBA in preventing the development and progression of atherosclerosis and promoting plaque stabilization.
Comments
N/A