Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction

Smith, Robert S.; Agata, Jun; Xia, Chun‐Fang; Chao, Lee; Chao, Julie

doi:10.1016/j.lfs.2004.11.028

Cited by 85 publications

(58 citation statements)

References 53 publications

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“…The increase in oxidative stress in ob/ob mice was not related to NADPH oxidase, which is another important source of ROS in the heart [23], as the expression of its subunits was similar between ob/ob mice and controls. Besides that, NADPH oxidase is reported to be linked to NOS3 [25] and both protein abundance and mRNA expression of NOS3 were unaltered by leptin deficiency. Another important aspect in NOS1 cardiobiology in disease states is its translocation from SR to sarcolemmal membranes [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

“…In the heart, NO synthase (NOS) isoforms are compartmentalized to specific subcellular microdomains and are involved in many aspects of cardiac excitation-contraction coupling and energetics [20][21][22]. The balance between the production of reactive oxygen species (ROS) and nitrogen species (RNS) -nitroso-redox balance -is a proposed mechanism for the regulation of multiple functions inside the cell in normal and pathological conditions [23;24], and both endothelial NOS (NOS3) [25][26][27][28] and neuronal NOS (NOS1) [29;30] isoforms are protective in cardiac disease. NOS1 participates in several critical physiologic cardiac processes.…”

Section: Introductionmentioning

confidence: 99%

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Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

et al. 2007

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Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (ob/ob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2-6 month old ob/ob (n=26) and C57Bl/6 controls (n=27). Cardiac NOS1 protein abundance (P<0.01) and mRNA expression (P=0.03) were reduced in ob/ob (n=10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in ob/ob mice after leptin treatment (n=3; P<0.05 vs leptin untreated ob/ob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in ob/ob mice (n=5; P=0.02). Furthermore, oxidative stress was increased in ob/ob mice as GSH/ GSSG ratio was decreased (n=4; P=0.02). Whereas XOR activity measured by Amplex Red fluorescence assay kit was increased (n=8; P=0.04), XOR and NADPH oxidase subunits protein abundance were not changed in ob/ob mice (n=6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

et al. 2007

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“…The activation of NF-B p50 subunit in response to Ang II in endothelial cells is controversial. Some investigators 20,21 have shown the activation of both p50 and p65 subunits by Ang II, whereas others 16,22 showed the activation of only NF-B p65 by Ang II. We performed EMSA-supershift assay with antibody against NF-B p50 subunit, and found that Ang IIinduced shifted band was somewhat attenuated by the NF-B p50 antibody (data not shown).…”

Section: The Critical Role Of Nf-b In Ang Ii-induced Lox-1 Promoter Amentioning

confidence: 99%

Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter

Chen

Liu

et al. 2006

ATVB

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Objective-LOX-1, a receptor for oxidized low-density lipoprotein, plays a critical role in atherosclerosis. Its expression is upregulated by pro-atherogenic stimuli, such as angiotensin II (Ang II). In this study, we explored LOX-1 transcriptional promoter activation in response to Ang II in human coronary artery endothelial cells (HCAECs). Methods and Results-We constructed full-length and deletion LOX-1 promoter mutants and examined their activation in response to Ang II in HCAECs. The Ang II (1 mol/L for 24 hours) markedly induced LOX-1 promoter activity beyond the basal level, and a 116-bp fragment (between nt Ϫ2247 and Ϫ2131) was necessary for this induction. Key Words: LOX-1 Ⅲ Ang II Ⅲ oxLDL Ⅲ transcription factor Ⅲ NF-B Ⅲ oxidative stress A therosclerosis and associated diseases are major causes of death in the Western world. High plasma level of low-density lipoprotein (LDL), especially in the form of oxidized LDL (oxLDL), is a major risk factor for atherogenesis. 1 oxLDL plays a critical role in endothelial dysfunction, which appears at the early stages of atherogenesis. 2 In vitro studies have demonstrated that during oxLDL-induced endothelial dysfunction, vascular endothelial cells internalize ox-LDL through a receptor-mediated pathway. Although several scavenger receptors are involved in the internalization of oxLDL in macrophages, these receptors are absent or present only in a very small amount on endothelial cells. 3 Recently, an endothelial oxLDL receptor, LOX-1, was identified on cultured bovine aortic endothelial cells 4 and human coronary artery endothelial cells (HCAECs). 5 Many of the proatherogenic effects of oxLDL in endothelial cells appear to be mediated through LOX-1. 6 In vitro and in vivo studies have shown that LOX-1 expression is upregulated by oxLDL. 7,8 Angiotensin II (Ang II), which participates in atherogenesis, 9 also upregulates the expression of LOX-1. 10 Singh and Mehta 11 recently proposed an interaction between hyperlipidemia and renin-angiotensin system (RAS) activation in the development of atherosclerosis, during which LOX-1 plays a critical role.The nucleotide sequence of human LOX-1 promoter has been identified. 12 Although only a few details are known about the transcription factors that modulate LOX-1 gene expression, a number of potential cis-regulatory elements, such as nuclear factor-B (NF-B) and activator protein-1 (AP-1) binding motif, are found within the LOX-1 promoter sequence. 12 Nonetheless, human LOX-1 transcriptional promoter has not been thoroughly examined on the molecular level.In a recent study, we examined LOX-1 promoter activation in response to oxLDL in HCAECs, and found the transcription factor octamer-1(Oct-1) is essential for this process. 13 To delineate whether Ang II activates LOX-1 promoter through this (Oct-1) or another pathway, we analyzed Ang II-mediated activation of human LOX-1 promoter in HCAECs. Methods and Materials LOX-1 Promoter-Luciferase Reporter Plasmid ConstructionThe promoterless luciferase reporter vector (pGL3 Basic) was o...

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“…Gene therapy has been explored for the treatment and protection of cardiomyocytes (Frank et al, 2005;Ren et al, 2004;Schroder et al, 2004;Smith et al, 2005). For example, human endothelial nitric oxide synthase gene delivery was shown to protect the cardiomyocytes against cardiac remodeling and reduce oxidative stress (Smith et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…For example, human endothelial nitric oxide synthase gene delivery was shown to protect the cardiomyocytes against cardiac remodeling and reduce oxidative stress (Smith et al, 2005). The p35 gene was delivered to cardiomyocytes for alleviating doxorubicin-induced cardiomyopath (Date et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Biodegradable cationic polyester as an efficient carrier for gene delivery to neonatal cardiomyocytes

et al. 2006

Biotech & Bioengineering

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Viral-mediated gene delivery has been explored for the treatment and protection of cardiomyocytes, but so far there is only one report using cationic polymer for gene delivery to cardiomyocytes in spite of many advantages of polymer-mediated gene delivery. In this study, a cationic poly(b-amino ester) (PDMA) with a degradable backbone and cleavable side chains was synthesized by Michael addition reaction. The toxicity of PDMA to neonatal mouse cardiomyocytes (NMCMs) was significantly lower than that of polyethyleneimine (PEI). PDMA formed stable polyplexes with pEGFP. The dissociation of the polyplexes could be triggered by PDMA degradation, and the dissociation time was tunable via the polymer/pEGFP ratio. In vitro transfection showed that PDMA was an effective and low toxic gene delivery carrier for NMCMs. The PDMA/pEGFP polyplexes transfected EGFP gene to NMCMs with about 28% efficiency and caused little death. In contrast, a significant portion of cardiomyocytes cultured with PEI/pEGFP died.

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Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction

Cited by 85 publications

References 53 publications

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter

Biodegradable cationic polyester as an efficient carrier for gene delivery to neonatal cardiomyocytes

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