Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

Liu, Yilin; Neumann, Dietbert; Glatz, Jan F. C.; Luiken, Joost J. F. P.

doi:10.1016/j.plefa.2016.06.002

Cited by 29 publications

(27 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ceramides act as key components of lipotoxic signaling pathways linking lipid-induced inflammation with insulin signaling inhibition [157]. On other hand, high lipid contents can induce contractile dysfunction independently of insulin resistance [158]. Therefore, the resultant defect in myocardial energy production impairs myocyte contraction and diastolic function [93, 159] (Fig.…”

Section: Insulin Resistance and Changes In The Cardiac Metabolismmentioning

confidence: 99%

Association between insulin resistance and the development of cardiovascular disease

Ormazábal

Nair

Elfeky

et al. 2018

Cardiovasc Diabetol

1,421

950

View full text Add to dashboard Cite

For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

show abstract

Section: Insulin Resistance and Changes In The Cardiac Metabolismmentioning

confidence: 99%

Association between insulin resistance and the development of cardiovascular disease

Ormazábal

Nair

Elfeky

et al. 2018

Cardiovasc Diabetol

1,421

950

View full text Add to dashboard Cite

show abstract

“…There is also experimental evidence on the role of different ceramide species in several atherosclerotic processes such as aggregation of lipoproteins, accumulation of lipoproteins and cholesterol within macrophages and vessel wall, impairment of mitochondrial function leading to excessive production of ROS, regulation of NO synthesis, activation of platelets, and expression of various cytokines [70,134,142,155]. Moreover, ceramides also modulate signaling and metabolic pathways involved not only on insulin resistance, but also on hepatic steatosis, and hypertension and, therefore, play a key role in the metabolic dysfunction that precedes cardiovascular events [138,139,140,160,161]. Finally, some ceramides may trigger cardiomyocyte-specific actions leading to the so termed lipotoxic cardiomyopathy [155,160,162].…”

Section: Ceramide and Diseasementioning

confidence: 99%

Ceramide and Regulation of Vascular Tone

Cogolludo

Villamor

Pérez‐Vizcaíno

et al. 2019

IJMS

View full text Add to dashboard Cite

In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases.

show abstract

“…Elevated ROS levels consume and surpass the antioxidant capacity of the injured myocardium, significantly contributing to oxidative stress generation and affecting protein function, resulting in myocardial damage with morphological and functional abnormalities [ 13 ]. In cardiac I/R injury, significant sources of ROS are inflammation-induced phagocyte-type NAD (P) H oxidase and mitochondrial metabolism-associated fatty acid oxidation [ 14 , 15 ]. Excessive ROS generation opens the mitochondrial permeability transition pore (MPTP) further contributing to myocardial injury and contractile dysfunction.…”

Section: Introductionmentioning

confidence: 99%

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice

Habicht

Mohsen

Eichhorn

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Objective. Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. Methods. C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. Results. DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3±0.4 CD vs. 1.4±0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0±0.6 CD vs. 1.5±0.2 DHA), IL-1β (60.7±7.0 CD vs. 11.6±1.9 DHA), and IL-10 (223.8±62.1 CD vs. 135.5±38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/β myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8±11.5 CD vs. 78.8±13.6 DHA) but terminated earlier (CCL2 72 h: 39.5±7.8 CD vs. 8.2±1.9 DHA; CCL3 72 h: 794.3±270.9 CD vs. 258.2±57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6±2.6 CD vs. 31.4±1.5 DHA). Conclusion. Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to β-MHC isoform switch.

show abstract

Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

Cited by 29 publications

References 118 publications

Association between insulin resistance and the development of cardiovascular disease

Association between insulin resistance and the development of cardiovascular disease

Ceramide and Regulation of Vascular Tone

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice

Contact Info

Product

Resources

About