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Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

ABSTRACT: OBJECTIVE:Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression of profurin, the 83-amino acid prodomain of the proprotein convertase furin, lowered plasma HDL levels in wild-type mice. The question that remained was whether it had effects on apolipoprotein B (ApoB)-containing lipoproteins. METHODS:Adenovirus mediated overexpression of hepatic profurin in Ldlr(-/-)mice and wild-type mice were used to evaluate effects of profurin on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling. RESULTS:Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr(-/-)mice and a robust reduction in plasma LDL-c. Metabolic studies revealed lower secretion of ApoB and triglycerides in VLDL particles. Mechanistic studies showed that in the presence of profurin, hepatic ApoB, mainly ApoB100, was degraded by proteasomes. There was no effect on ApoB mRNA expression. Importantly, short-term hepatic profurin overexpression did not result in hepatic lipid accumulation. Blood vessel wall thickening caused by either wire-induced femoral artery injury or common carotid artery ligation was reduced. Profurin expression inhibited proliferation and migration in vascular smooth muscle cells in vitro. CONCLUSION:These results indicate that a profurin-based therapy has the potential to treat atherosclerosis by improving metabolic lipid profiles and reducing both atherosclerotic lesion development and pathological vascular remodeling.

SUBMITTER: Lei X

PROVIDER: S-EPMC7518654 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

Lei Xia X Basu Debapriya D Li Zhiqiang Z Zhang Maoxiang M Rudic R Dan RD Jiang Xian-Cheng XC Jin Weijun W

Atherosclerosis 20140701 1

<h4>Objective</h4>Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression of profurin, the 83-amino acid prodom ...[more]

PMID: 25026302

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Project description:Heart failure (HF) is a functional lack of myocardial performance due to a loss of molecular control over increases in calcium and ROS, resulting in proteolytic degradative advances and cardiac remodeling. Mitochondria are the molecular powerhouse of cells, shifting the sphere of cardiomyocyte stability and performance. Functional mitochondria rely on the molecular abilities of safety factors such as TFAM to maintain physiological parameters. Mitochondrial transcription factor A (TFAM) creates a mitochondrial nucleoid structure around mtDNA, protecting it from mutation, inhibiting NFAT (ROS activator/hypertrophic stimulator), and transcriptionally activates Serca2a to decrease calcium mishandling. Calpain1 and MMP9 are proteolytic degratory factors that play a major role in cardiomyocyte decline in HF. Current literature depicts major decreases in TFAM as HF progresses. We aim to assess TFAM function against Calpain1 and MMP9 proteolytic activity and its role in cardiac remodeling. To this date, no publication has surfaced describing the effects of aortic banding (AB) as a surgical HF model in TFAM-TG mice. HF models were created via AB in TFAM transgenic (TFAM-TG) and C57BLJ-6 (WT) mice. Eight weeks post AB, functional analysis revealed a successful banding procedure, resulting in cardiac hypertrophy as observed via echocardiography. Pulse wave and color doppler show increased aortic flow rates as well as turbulent flow at the banding site. Preliminary results of cardiac tissue immuno-histochemistry of HF-control mice show decreased TFAM and compensatory increases in Serca2a fluorescent expression, along with increased Calpain1 and MMP9 expression. Protein, RNA, and IHC analysis will further assess TFAM-TG results post-banding. Echocardiography shows more cardiac stability and functionality in HF-induced TFAM-TG mice than the control counterpart. These findings complement our published in vitro results. Overall, this suggests that TFAM has molecular therapeutic potential to reduce protease expression.

Project description:BackgroundInflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis.Methods and resultsIn mice with early atherosclerosis (Apoe-/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages.ConclusionsOur data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk.

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Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

Publications

Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

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