Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

Dato, Virginia Actis; Benitez‐Amaro, Aleyda; García, Eduardo García; Claudi, Lene; Lhoëst, Maria Teresa LaChica; Iborra, A.; Escolà‐Gil, Joan Carles; Guerra, José M.; Samouillan, Valérie; Enrich, Carlos; Chiabrando, Gustavo A.; Llorente‐Cortés, Vicenta

doi:10.1016/j.biopha.2022.113270

Cited by 5 publications

(22 citation statements)

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“…45 Our results from this translational rabbit model suggest that the cardiomyocyte LD-CE content may influence the ECM composition. Therefore, we explored in this model whether anti-P3 Abs, with specifically reduce the level of accumulation of intracellular CE in rabbit cardiomyocytes, 18 reverse HFDinduced biophysical ECM alterations in the heart. Effect of Anti-P3 Abs on HFD-Induced Changes in the Biophysical ECM Structure and Composition.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Considering that intramyocardial CE accumulation in the heart is promoted by high-prevalence pathological situations, including ischemia, − hypercholesterolemia, − and obesity, all of them associated with dyslipemia, LRP1-based immunotherapy emerges as a valuable strategy for modulating not only cardiac sensitivity but also cardiac fibrosis in these groups of patients. However, additional and/or complementary strategies are required to avoid the pathological ECM plasticization associated with dyslipidemia.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 Biophysical studies allowed us to identify the spectral lipid Fourier transform infrared (FTIR) signatures of circulating LDL and VLDL in the heart of hypercholesterolemic rabbits. 18 These results highlight the crucial effects of hypercholesterolemia and CE-enriched lipoproteins in the electrical and metabolic remodeling of the heart. Ventricular dysfunction in patients with heart failure is associated with cardiac fibrosis, an excessive deposition of extracellular matrix (ECM) proteins.…”

Section: ■ Introductionmentioning

confidence: 99%

“…LRP1 is a key receptor involved in the selective uptake of CE from CE-enriched lipoproteins in vascular cells. , Through molecular, structural, and proteomic studies, we determined one specific LRP1 sequence that interacts with ApoB100. , On the basis of this information, we developed an LRP1 (P3)-based immunotherapy with specificity and selectively to inhibit the accumulation of CE in vascular smooth and cardiac muscle cells in vivo in a rabbit model of hypercholesterolemia. , This immunotherapy increases the serum levels of anti-P3 Abs that efficiently compete with CE-enriched lipoproteins inhibiting atherosclerosis in vasculature and increasing insulin sensitivity in the heart of the rabbit model . This unique rabbit model offers the possibility of testing the pathological and specific impact of intracellular CE accumulation in processes related to cardiac functionality such as extracellular matrix composition, fibrosis, and plasticization.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

et al. 2023

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The accumulation of lipids in cardiomyocytes contributes to cardiac dysfunction. The specific blockage of cardiomyocyte cholesteryl ester (CE) loading by antibodies (Abs) against the P3 sequence (Gly 1127 −Cys 1140 ) of the LRP1 receptor improves cardiac insulin sensitivity. The impact of anti-P3 Abs on high-fat diet (HFD)-induced cardiac extracellular matrix (ECM) biophysical alterations was analyzed. Both IrP (without Abs) and P3immunized rabbits (with Abs) were randomized into groups fed either HFD or a standard chow diet. Cardiac lipids, proteins, and carbohydrates were characterized by Fourier transform infrared spectroscopy in the attenuated total reflectance mode. The hydric organization and physical structure were determined by differential scanning calorimetry. HFD increased the levels of esterified lipids, collagen, and α-helical structures and upregulated fibrosis, bound water, and ECM plasticization in the heart. The inhibitory effect of anti-P3 Abs on cardiac CE accumulation was sufficient to reduce the collagen-filled extracellular space, the level of fibrosis, and the amount of bound water but did not counteract ECM plasticization in the heart of hypercholesterolemic rabbits.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

et al. 2023

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“…Lipotoxicity derived from myocardial lipid accumulation may partially contribute to cardiac dysfunction [44], as shown in this study. Moreover, it has been reported that targeting cholesteryl ester accumulation in the heart improves cardiac insulin response [45]. Thus, fat accumulation including TGs as well as cholesteryl ester accumulation in myocardium may be a therapeutic target for type 2 diabetes patients with heart failure.…”

Section: Relationships Between Myocardial Fat and Obesity Related Fac...mentioning

confidence: 99%

Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study

Kashiwagi-Takayama

Kozawa

Hosokawa

et al. 2023

Cardiovasc Diabetol

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Background Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. Methods We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. Results In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = − 0.1923, − 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e’) (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e’ in these subgroups (p < 0.05). Conclusions Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.

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Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality

Dato

Paz

Rey

et al. 2023

Sci Rep

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Cardiovascular disease (CVD) is a multisystemic and multicellular pathology that is generally associated with high levels of atherogenic lipoproteins in circulation. These lipoproteins tend to be retained and modified, for example, aggregated low-density lipoprotein (aggLDL), in the extracellular matrix of different tissues, such as the vascular wall and heart. The uptake of aggLDL generates a significant increase in cholesteryl ester (CE) in these tissues. We previously found that the accumulation of CE generates alterations in the insulin response in the heart. Although the insulin response is mainly associated with the uptake and metabolism of glucose, other studies have shown that insulin would fulfill functions in this tissue, such as regulating the calcium cycle and cardiac contractility. Here, we found that aggLDL induced-lipid accumulation altered the gene expression profile involved in processes essential for cardiac functionality, including insulin response and glucose uptake (Insr, Ins1, Pik3ip1, Slc2a4 gene expression), calcium cycle (Cacna1s and Gjc2 gene expression) and calcium-dependent cardiac contractility (Myh3), and cholesterol efflux (Abca1), in HL-1 cardiomyocytes. These observations were recapitulated using an in vivo model of hypercholesterolemic ApoE-KO mice. Altogether, these results may explain the deleterious effect of lipid accumulation in the myocardium, with important implications for lipid-overloaded associated CVD, including impaired insulin response, disrupted lipid metabolism, altered cardiac structure, and increased susceptibility to cardiovascular events.

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Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

Cited by 5 publications

References 58 publications

Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study

Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality

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