Increased Remnant Lipoproteins in Apo E Deficient Mice Induce Coronary Atherosclerosis following Transverse Aortic Constriction and Aggravate the Development of Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure.

Murine coronary arteries are very resistant to the development of atherosclerosis, which may be related to their intramyocardial course. Blood pressure promotes atherosclerotic plaque formation by acting as a physical force that potentiates the migration of pro-atherogenic lipoproteins across the endothelium. C57BL/6N apolipoprotein (apo) E deficient mice have increased remnant lipoproteins that are a risk factor for coronary atherosclerosis.

Developing a second-generation clinical candidate AAV vector for gene therapy of familial hypercholesterolemia.

Gene therapy for hypercholesterolemia offers the potential to sustainably ameliorate disease for life with a single dose. In this study, we demonstrate the combinatorial effects of codon and vector optimization, which significantly improve the efficacy of an adeno-associated virus (AAV) vector in the low-density lipoprotein receptor (LDLR)-deficient mouse model ( , double knockout [DKO]). This study investigated vector efficacy following the combination of intervening sequence 2 (IVS2) of the human beta-globin gene and codon optimization with the previously developed gain-of-function, human LDLR triple-mutant variant (hLDLR-L318D/K809R/C818A) in the treatment of homozygous familial hypercholesterolemia (HoFH).

Administration of apo A-I (Milano) nanoparticles reverses pathological remodelling, cardiac dysfunction, and heart failure in a murine model of HFpEF associated with hypertension.

Therapeutic interventions with proven efficacy in heart failure with reduced ejection fraction (HFrEF) have been unsuccessful in heart failure with preserved ejection fraction (HFpEF). The modifiable risk factor with the greatest impact on the development of HFpEF is hypertension. The objectives of this study were to establish a murine model of HFpEF associated with hypertension and to evaluate the effect of apo A-I nanoparticles (MDCO-216) on established HFpEF in this model.

Cholesterol lowering attenuates pressure overload-induced heart failure in mice with mild hypercholesterolemia.

Epidemiological studies support a strong association between non-high-density lipoprotein cholesterol levels and heart failure incidence. The objective of the current study was to evaluate the effect of selective cholesterol lowering adeno-associated viral serotype 8 (AAV8)-mediated gene transfer on cardiac remodelling and myocardial oxidative stress following transverse aortic constriction (TAC) in female C57BL/6 LDLr mice with mild hypercholesterolemia. Cholesterol lowering gene transfer resulted in a 65.

Cholesterol-Lowering Gene Therapy Prevents Heart Failure with Preserved Ejection Fraction in Obese Type 2 Diabetic Mice.

Hypercholesterolemia may be causally related to heart failure with preserved ejection fraction (HFpEF). We aimed to establish a HFpEF model associated with hypercholesterolemia and type 2 diabetes mellitus by feeding a high-sucrose/high-fat (HSHF) diet to C57BL/6J low-density lipoprotein receptor (LDLr) mice. Secondly, we evaluated whether cholesterol-lowering adeno-associated viral serotype 8 (AAV8)-mediated LDLr gene transfer prevents HFpEF.

Effective Treatment of Diabetic Cardiomyopathy and Heart Failure with Reconstituted HDL (Milano) in Mice.

The risk of heart failure (HF) is prominently increased in patients with type 2 diabetes mellitus. The objectives of this study were to establish a murine model of diabetic cardiomyopathy induced by feeding a high-sugar/high-fat (HSHF) diet and to evaluate the effect of reconstituted HDL administration on established HF in this model. The HSHF diet was initiated at the age of 12 weeks and continued for 16 weeks.

Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice.

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) (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.

Successful treatment of established heart failure in mice with recombinant HDL (Milano).

Background And Purpose: The pleiotropic properties of HDL may exert beneficial effects on the myocardium. The effect of recombinant HDL on established heart failure was evaluated in C57BL/6 mice.

Experimental Approach: Mice were subjected to transverse aortic constriction (TAC) or sham operation at the age of 14 weeks.

Hepatocyte-Specific SR-BI Gene Transfer Corrects Cardiac Dysfunction in Scarb1-Deficient Mice and Improves Pressure Overload-Induced Cardiomyopathy.

Objective- We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in Scarb1 mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in Scarb1 mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function. Approach and Results- Transverse aortic constriction (TAC) or sham operation was performed at the age of 14 weeks, 2 weeks after saline injection or after gene transfer with AdSR-BI or with the control vector Adnull.

Selective HDL-Raising Human Apo A-I Gene Therapy Counteracts Cardiac Hypertrophy, Reduces Myocardial Fibrosis, and Improves Cardiac Function in Mice with Chronic Pressure Overload.

Epidemiological studies support an independent inverse association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. The effect of selective HDL-raising adeno-associated viral serotype 8-human apolipoprotein (apo) A-I (AAV8-A-I) gene transfer on cardiac remodeling induced by transverse aortic constriction (TAC) was evaluated in C57BL/6 low-density lipoprotein receptor-deficient mice. Septal wall thickness and cardiomyocyte cross-sectional area were reduced by 16.

Cholesterol-Lowering Gene Therapy Counteracts the Development of Non-ischemic Cardiomyopathy in Mice.

A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.

Coconut Oil Aggravates Pressure Overload-Induced Cardiomyopathy without Inducing Obesity, Systemic Insulin Resistance, or Cardiac Steatosis.

Studies evaluating the effects of high-saturated fat diets on cardiac function are most often confounded by diet-induced obesity and by systemic insulin resistance. We evaluated whether coconut oil, containing C12:0 and C14:0 as main fatty acids, aggravates pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC) in C57BL/6 mice. Mortality rate after TAC was higher ( < 0.

Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice.

Background: Obesity is associated with vascular inflammation, fibrosis and reduced high-density lipoproteins (HDL)-cholesterol. We aimed to investigate whether adenoviral gene transfer with human apolipoprotein (apo) A-I (Ad.A-I), the main apo of HDL, could exert immunomodulatory effects and counteract vascular inflammation and fibrosis in ob/ob mice.

Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress.

Unlabelled: Plasma homocysteine levels predict heart failure incidence in prospective epidemiological studies. We evaluated whether selective homocysteine-lowering gene transfer beneficially affects cardiac remodeling and function in a model of pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC). Female C57BL/6 low-density lipoprotein receptor (Ldlr (-/-)) cystathionine-β-synthase (Cbs (+/-)) mice were fed standard chow (control mice) or a folate-depleted, methionine-enriched diet to induce hyperhomocysteinemia (diet mice).

Permanent ligation of the left anterior descending coronary artery in mice: a model of post-myocardial infarction remodelling and heart failure.

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality.

The Impact of Lipoproteins on Wound Healing: Topical HDL Therapy Corrects Delayed Wound Healing in Apolipoprotein E Deficient Mice.

Chronic non-healing wounds lead to considerable morbidity and mortality. Pleiotropic effects of high density lipoproteins (HDL) may beneficially affect wound healing. The objectives of this murine study were: (1) to investigate the hypothesis that hypercholesterolemia induces impaired wound healing and (2) to study the effect of topical HDL administration in a model of delayed wound healing.

Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and enhances diastolic function after myocardial infarction in mice.

Background And Aims: Homocysteine levels predict heart failure incidence in prospective epidemiological studies and correlate with severity of heart failure in cross-sectional surveys. The objective of this study was to evaluate whether a selective homocysteine lowering intervention beneficially affects cardiac remodelling and cardiac function after myocardial infarction (MI) in a murine model of combined hypercholesterolemia and hyperhomocysteinemia.

Methodology And Principal Findings: A selective homocysteine lowering gene transfer strategy was evaluated in female C57BL/6 low density lipoprotein receptor (Ldlr)⁻/⁻ cystathionine-ß-synthase (Cbs)⁺/⁻ deficient mice fed a hyperhomocysteinemic and high saturated fat/high cholesterol diet using an E1E3E4-deleted hepatocyte-specific adenoviral vector expressing Cbs (AdCBS).

Lipid lowering and HDL raising gene transfer increase endothelial progenitor cells, enhance myocardial vascularity, and improve diastolic function.

Background: Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC) number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr(-/-)) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function.

Protein tyrosine phosphatase SHP2 mediates chronic insulin-induced endothelial inflammation.

Objective: Insulin promotes adhesion of leukocytes to the endothelium through increased expression of surface adhesion molecules. We determined whether src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), a downstream effecter of insulin signaling, is involved in insulin-induced endothelial inflammation.

Methods And Results: In human umbilical vein-derived endothelial cells, treatment with insulin (100 nmol/L) increased Tyr(542) phosphorylation, activity, and subsequently expression of SHP2.

The liver as a target organ for gene therapy: state of the art, challenges, and future perspectives.

The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking.

Correction of endothelial dysfunction after selective homocysteine lowering gene therapy reduces arterial thrombogenicity but has no effect on atherogenesis.

Hyperhomocysteinemia is an independent risk factor for ischemic cardiovascular diseases, but its causal role in atherothrombosis remains controversial. Proatherogenic and/or prothrombotic effects may underlie the potential causal relation between hyperhomocysteinemia and cardiovascular events. Here, the effects of selective lowering of plasma homocysteine, plasma cholesterol, or both on endothelial function and on atherogenesis in male hyperlipidemic and hyperhomocysteinemic C57BL/6 low-density lipoprotein receptor (LDLr)(-/-)/cystathionine-β-synthase (CBS)(+/-)-deficient mice were investigated.