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Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl2. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.

Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl2. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions.

Abstract Background ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in β-amyloid (Aβ) fibrillization and clearance in the context of Alzheimer’s disease has been widely studied, although the source and concentration of ApoJ that promotes or inhibits Aβ cerebral accumulation is not clear yet. ApoJ is abundant in plasma and approximately 20% can appear bound to HDL-particles. In this regard, the impact of plasmatic ApoJ and its lipidation status on cerebral β-amyloidosis is still not known. Hence, our main objective was to study the effect of a peripheral increase of free ApoJ or reconstituted HDL particles containing ApoJ in an experimental model of cerebral β-amyloidosis. Methods Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1 month. Aβ concentration and distribution in the brain, as well as Aβ levels in plasma and CSF, were determined after treatments. Other features associated to AD pathology, such as neuronal loss and neuroinflammation, were also evaluated. Results Both ApoJ-based treatments prevented the Aβ accumulation in cerebral arteries and induced a decrease in total brain insoluble Aβ42 levels. The peripheral treatment with rApoJ also induced an increase in the Aβ40 levels in CSF, whereas the concentration remained unaltered in plasma. At all the endpoints studied, the lipidation of rApoJ did not enhance the protective properties of free rApoJ. The effects obtained after subchronic treatment with free rApoJ were accompanied by a reduction in hippocampal neuronal loss and an enhancement of the expression of a phagocytic marker in microglial cells surrounding Aβ deposits. Finally, despite the activation of this phagocytic phenotype, treatments did not induce a global neuroinflammatory status. In fact, free rApoJ treatment was able to reduce the levels of interleukin-17 (IL17) and keratinocyte chemoattractant (KC) chemokine in the brain. Conclusions Our results demonstrate that an increase in circulating human rApoJ induces a reduction of insoluble Aβ and CAA load in the brain of APP23 mice. Thus, our study suggests that peripheral interventions, based on treatments with multifunctional physiological chaperones, offer therapeutic opportunities to regulate the cerebral Aβ load.

Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.

Apolipoproteins are critical structural and functional components of lipoproteins, which are large supramolecular assemblies composed predominantly of lipids and proteins, and other biomolecules such as nucleic acids. A signature feature of apolipoproteins is the preponderance of amphipathic α-helical motifs that dictate their ability to make extensive non-covalent inter- or intra-molecular helix–helix interactions in lipid-free states or helix–lipid interactions with hydrophobic biomolecules in lipid-associated states. This review focuses on the latter ability of apolipoproteins, which has been capitalized on to reconstitute synthetic nanoscale binary/ternary lipoprotein complexes composed of apolipoproteins/peptides and lipids that mimic native high-density lipoproteins (HDLs) with the goal to transport drugs. It traces the historical development of our understanding of these nanostructures and how the cholesterol accepting property of HDL has been reconfigured to develop them as drug-loading platforms. The review provides the structural perspective of these platforms with different types of apolipoproteins and an overview of their synthesis. It also examines the cargo that have been loaded into the core for therapeutic and imaging purposes. Finally, it lays out the merits and challenges associated with apolipoprotein-based nanostructures with a future perspective calling for a need to develop “zip-code”-based delivery for therapeutic and diagnostic applications.

Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need. This study investigated whether feeding coconut oil (CC diet) for 26 weeks in female C57BL/6N mice induces HFpEF and evaluated the effect of reconstituted high-density lipoprotein (HDL)Milano (MDCO-216) administration on established HFpEF. Eight intraperitoneal injections of MDCO-216 (100 mg/kg protein concentration) or of an equivalent volume of control buffer were executed with a 48-h interval starting at 26 weeks after the initiation of the diet. Feeding the CC diet for 26 weeks induced pathological left ventricular hypertrophy characterized by a 17.1% (p < 0.0001) lower myocardial capillary density and markedly (p < 0.0001) increased interstitial fibrosis compared to standard chow (SC) diet mice. Parameters of systolic and diastolic function were significantly impaired in CC diet mice resulting in a reduced stroke volume, decreased cardiac output, and impaired ventriculo-arterial coupling. However, ejection fraction was preserved. Administration of MDCO-216 in CC diet mice reduced cardiac hypertrophy, increased capillary density (p < 0.01), and reduced interstitial fibrosis (p < 0.01). MDCO-216 treatment completely normalized cardiac function, lowered myocardial acetyl-coenzyme A carboxylase levels, and decreased myocardial transforming growth factor-β1 in CC diet mice. In conclusion, the CC diet induced HFpEF. Reconstituted HDLMilano reversed pathological remodeling and functional cardiac abnormalities.

The molecular mechanism by which nascent HDL forms via the interaction of apolipoprotein A-I (apoA-I) and transmembrane ABCA1 is poorly understood. Here, because ABCA1 has been reported to localize to acidic intracellular compartments, including the Golgi and endosome, we studied the interaction of apoA-I with model membranes under acidic conditions. Pure phosphatidylcholine liposomes were persistent against apoA-I at pH levels above 5.0, but were progressively transformed into reconstituted HDLs (rHDLs) by apoA-I at lower pH. Circular dichroism spectral measurements and 8-anilino-1-naphthalenesulfonic acid fluorescence measurements of lipid-free apoA-I ascribed this accelerated rHDL formation to the conformational change of the protein into a rather hydrophobic α-helical structure under acidic conditions. The addition of phosphatidylserine (PS) increased acidity at the bilayer surface and enabled the formation of discoidal rHDLs even at the pH of the endosome and slightly lower pH of the Golgi. These results suggest the following new scenario of nascent HDL formation: ABCA1, which colocalizes with apoA-I in acidic intracellular compartments, including the Golgi and endosome, increases acidity at the membrane surface on the luminal side by PS translocase activity and causes apoA-I to form nascent HDL.

Although many acute and chronic diseases are managed via pharmacological means, challenges remain regarding appropriate drug targeting and maintenance of therapeutic levels within target tissues. Advances in nanotechnology will overcome these challenges through the development of lipidic particles, including liposomes, lipoproteins, and reconstituted high-density lipoproteins (rHDL) that are potential carriers of water-soluble, hydrophobic, and amphiphilic molecules. Herein we summarize the properties of human plasma lipoproteins and rHDL, identify the physicochemical determinants of lipid transfer between phospholipid surfaces, and discuss strategies for increasing the plasma half-life of lipoprotein- and liposome-associated molecules. [ABSTRACT FROM AUTHOR]

Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60 mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24 h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7 days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. [ABSTRACT FROM AUTHOR]

Val156 of apolipoprotein A-I (apoA-I) was found to be a key amino acid in the structure and function of high density lipoprotein (HDL) (J. Biol. Chem., 275: 26821–26827, 2000). To determine more precisely the functions of the individual amino acids proximal to Val156, serial point mutants of proapoA-I, including V156K, D157K, and A158E, were overexpressed and purified to at least 95% purity. In the lipid-free state, A158E exhibited the most profound self-associative patterns and the least pronounced dimyristoyl phosphatidylcholine (DMPC) clearance activities. In the lipid-bound state, A158E formed a larger reconstituted HDL (rHDL) with palmitoyloleoyl phosphatidylcholine (POPC), ∼120 Å, whereas other mutants and the wild type (WT) formed 97 Å of POPC-rHDL. Cross-linking analysis revealed that A158E-rHDL harbored at least four protein molecules in the particle, while other rHDL conformations contained only two protein molecules. All of the POPC-rHDL produced smaller HDL, around 78 Å, after 24 h of incubation in the presence of low density lipoprotein at 37°C. V156K and A158E exhibited decreased lecithin:cholesterol acyltransferase activation activity in the POPC-rHDL state, showing

Mast cell chymase, a chymotrypsin-like neutral protease, can proteolyze HDL3. Here we studied the ability of rat and human chymase to proteolyze discoidal preβ-migrating reconstituted HDL particles (rHDLs) containing either apolipoprotein A-I (apoA-I) or apoA-II. Both chymases cleaved apoA-I in rHDL at identical sites, either at the N-terminus (Tyr18 or Phe33) or at the C-terminus (Phe225), so generating three major truncated polypeptides that remained bound to the rHDL. The cleavage sites were independent of the size of the rHDL particles, but small particles were more susceptible to degradation than bigger ones. Chymase-induced truncation of apoA-I yielded functionally compromised rHDL with reduced ability to promote cellular cholesterol efflux. In sharp contrast to apoA-I, apoA-II was resistant to degradation. However, when apoA-II was present in rHDL that also contained apoA-I, it was degraded by chymase.We conclude that chymase reduces the ability of apoA-I in discoidal rHDL particles to induce cholesterol efflux by cleaving off either its amino- or carboxy-terminal portion. This observation supports the concept that limited extracellular proteolysis of apoA-I is one pathophysiologic mechanism leading to the generation and maintenance of foam cells in atherosclerotic lesions.

Apolipoprotein A-I (apoA-I) is an important ligand for the high density lipoprotein (HDL) scavenger receptor class B type I (SR-BI). SR-BI binds both free and lipoprotein-associated apoA-I, but the effects of particle size, composition, and apolipoprotein conformation on HDL binding to SR-BI are not understood. We have studied the effect of apoA-I conformation on particle binding using native HDL and reconstituted HDL particles of defined composition and size. SR-BI expressed in transfected Chinese hamster ovary cells was shown to bind human HDL2 with greater affinity than HDL3, suggesting that HDL size, composition, and possibly apolipoprotein conformation influence HDL binding to SR-BI. To discriminate between these factors, SR-BI binding was studied further using reconstituted l-α-palmitoyloleoyl-phosphatidylcholine-containing HDL particles having identical components and equal amounts of apoA-I, but differing in size (7.8 vs. 9.6 nm in diameter) and apoA-I conformation. The affinity of binding to SR-BI was significantly greater (50-fold) for the larger (9.6-nm) particle than for the 7.8-nm particle. We conclude that differences in apoA-I conformation in different-sized particles markedly influence apoA-I recognition by SR-BI. Preferential binding of larger HDL particles to SR-BI would promote productive selective cholesteryl ester uptake from larger cholesteryl ester-rich HDL over lipid-poor HDL. —de Beer, M. C., D. M. Durbin, L. Cai, A. Jonas, F. C. de Beer, and D. R. van der Westhuyzen. Apolipoprotein A-I conformation markedly influences HDL interaction with scavenger receptor BI.

Previous studies have shown that both high density lipoproteins (HDL) isolated from human plasma and reconstituted HDL (rHDL) are effective inhibitors of adhesion molecule expression in human endothelial cells. In this study rHDL have been used to investigate whether HDL particle shape, size, apolipoprotein composition or lipid composition are important determinants of the ability of HDL to inhibit the TNF-α induced expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). On the basis of these studies it is possible to draw several firm conclusions. i) Neither phospholipid-containing vesicles nor lipid-free apolipoprotein (apo) A-I inhibit VCAM-1 expression in HUVECs. ii) Simple discoidal complexes containing only phospholipid and apoA-I (discoidal (A-I)rHDL) are sufficient to inhibit the TNF-α-induced expression of VCAM-1 in HUVECs. iii) Spherical apoA-I-containing rHDL (spherical (A-I)rHDL) are superior to discoidal (A-I)rHDL as inhibitors. iv) The particle size of spherical (A-I)rHDL has no influence on the inhibition. v) Spherical rHDL that contain apoA-I are superior as inhibitors of VCAM-1 to those containing apoA-II when the rHDL preparations are equated for apolipoprotein molarity. However, when compared at equivalent particle molarities, this difference is no longer apparent. vi) Replacement of cholesteryl esters with triglyceride in the core of spherical (A-I)rHDL has no effect on the ability of these particles to inhibit VCAM-1 expression. From these results it is tempting to speculate that variations in inhibitory activity may contribute to the variations observed in the anti-atherogenicity of different HDL subpopulations.—Baker, P. W., K-A. Rye, J. R. Gamble, M. A. Vadas, and P. J. Barter. Ability of reconstituted high density lipoproteins to inhibit cytokine-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. J. Lipid Res. 1999. 40: 345–353.

Apolipoproteins are critical structural and functional components of lipoproteins, which are large supramolecular assemblies composed predominantly of lipids and proteins, and other biomolecules such as nucleic acids. A signature feature of apolipoproteins is the preponderance of amphipathic α-helical motifs that dictate their ability to make extensive non-covalent inter- or intra-molecular helix–helix interactions in lipid-free states or helix–lipid interactions with hydrophobic biomolecules in lipid-associated states. This review focuses on the latter ability of apolipoproteins, which has been capitalized on to reconstitute synthetic nanoscale binary/ternary lipoprotein complexes composed of apolipoproteins/peptides and lipids that mimic native high-density lipoproteins (HDLs) with the goal to transport drugs. It traces the historical development of our understanding of these nanostructures and how the cholesterol accepting property of HDL has been reconfigured to develop them as drug-loading platforms. The review provides the structural perspective of these platforms with different types of apolipoproteins and an overview of their synthesis. It also examines the cargo that have been loaded into the core for therapeutic and imaging purposes. Finally, it lays out the merits and challenges associated with apolipoprotein-based nanostructures with a future perspective calling for a need to develop "zip-code"-based delivery for therapeutic and diagnostic applications. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DH declared a past co-authorship with one of the authors VF., (Copyright © 2021 Waldie, Sebastiani, Moulin, Del Giudice, Paracini, Roosen-Runge, Gerelli, Prevost, Voss, Darwish, Yepuri, Pichler, Maric, Forsyth, Haertlein and Cárdenas.)

Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1−/− × Apoe−/− mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need. This study investigated whether feeding coconut oil (CC diet) for 26 weeks in female C57BL/6N mice induces HFpEF and evaluated the effect of reconstituted high-density lipoprotein (HDL)Milano (MDCO-216) administration on established HFpEF. Eight intraperitoneal injections of MDCO-216 (100 mg/kg protein concentration) or of an equivalent volume of control buffer were executed with a 48-h interval starting at 26 weeks after the initiation of the diet. Feeding the CC diet for 26 weeks induced pathological left ventricular hypertrophy characterized by a 17.1% (p < 0.0001) lower myocardial capillary density and markedly (p < 0.0001) increased interstitial fibrosis compared to standard chow (SC) diet mice. Parameters of systolic and diastolic function were significantly impaired in CC diet mice resulting in a reduced stroke volume, decreased cardiac output, and impaired ventriculo-arterial coupling. However, ejection fraction was preserved. Administration of MDCO-216 in CC diet mice reduced cardiac hypertrophy, increased capillary density (p < 0.01), and reduced interstitial fibrosis (p < 0.01). MDCO-216 treatment completely normalized cardiac function, lowered myocardial acetyl-coenzyme A carboxylase levels, and decreased myocardial transforming growth factor-β1 in CC diet mice. In conclusion, the CC diet induced HFpEF. Reconstituted HDLMilano reversed pathological remodeling and functional cardiac abnormalities. [ABSTRACT FROM AUTHOR]