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1.
J Clin Invest ; 116(8): 2218-25, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16878172

ABSTRACT

The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II-dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II-induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure.


Subject(s)
Blood Pressure/physiology , Heart/physiology , Peptidyl-Dipeptidase A/deficiency , Peptidyl-Dipeptidase A/genetics , Angiotensin II/blood , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Blood Pressure/drug effects , Blood Pressure/genetics , Crosses, Genetic , Female , Fertility , Heart/drug effects , Infusions, Intravenous , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Reference Values
2.
J Heart Lung Transplant ; 24(1): 73-80, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15653383

ABSTRACT

BACKGROUND: Left ventricular assist devices (LVADs) implanted in patients with severe congestive heart failure (CHF) as a bridge to transplantation have been shown to reverse chamber enlargement, regress cellular hypertrophy, and increase contractility. The purpose of this study was to gain a better understanding of the molecular changes associated with increased contractility after LVAD support. METHODS: We took tissue sections from the left ventricular apex of 12 patients with CHF who were undergoing LVAD insertion (pre-LVAD) and from the LV free wall of those same patients before transplantation (post-LVAD). To control for sample-site differences, we obtained samples from the same regions in 7 patients with CHF who were undergoing transplantation without LVAD support and in 4 non- failing donor hearts. Gene expression was then probed on a custom DNA array containing 2,700 cardiac-enriched cDNA clones. RESULTS: Calcium-handling genes were up-regulated by LVAD support, as previously reported. Sarcomeric genes were the other principle class of genes up-regulated by LVAD support, consistent with a possible restoration of sarcomere structure in reverse ventricular remodeling. However, a decrease in the fibrous component of the myocardium, also potentially involved in reverse remodeling, was not evident at the level of gene transcription because fibroblast markers were either unchanged or up-regulated. The remaining regulated genes did not fall into any defined functional class. CONCLUSIONS: Changes in the regulation of sarcomeric, calcium-handling, and fibroblast genes during LVAD support indicate a cardiac molecular adaptation to mechanical unloading. These molecular changes may play a role in the observed increase in contractile function during reverse remodeling.


Subject(s)
Heart-Assist Devices , Ventricular Remodeling/genetics , Adult , Aged , Atrial Natriuretic Factor/genetics , Atrial Natriuretic Factor/metabolism , Blood Pressure/genetics , Connective Tissue Growth Factor , Female , Heart Failure/genetics , Heart Failure/surgery , Heart Transplantation , Heart Ventricles/metabolism , Heart Ventricles/surgery , Humans , Immediate-Early Proteins/genetics , Immediate-Early Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Myocardial Contraction/genetics , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Natriuretic Peptide, Brain/genetics , Natriuretic Peptide, Brain/metabolism , Osteonectin/genetics , Osteonectin/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stroke Volume/genetics , Transcription, Genetic/genetics , Up-Regulation/genetics
3.
Nature ; 432(7014): 173-8, 2004 Nov 11.
Article in English | MEDLINE | ID: mdl-15538359

ABSTRACT

RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.


Subject(s)
Apolipoproteins B/deficiency , Apolipoproteins B/genetics , Genetic Therapy/methods , RNA Interference/drug effects , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/pharmacology , Animals , Apolipoprotein B-100 , Apolipoproteins B/blood , Cholesterol/blood , Disease Models, Animal , Humans , Injections, Intravenous , Jejunum/drug effects , Jejunum/metabolism , Liver/drug effects , Liver/metabolism , Mice , Mice, Transgenic , RNA Processing, Post-Transcriptional/drug effects , RNA Stability , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/chemistry , RNA, Small Interfering/genetics , Sensitivity and Specificity
4.
J Mol Cell Cardiol ; 35(9): 1043-53, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12967627

ABSTRACT

Angiotensin converting enzyme related carboxypeptidase (ACE2) is a recently discovered homolog of angiotensin converting enzyme with tissue-restricted expression, including heart, and the capacity to cleave angiotensin peptides. We tested the hypothesis that cardiac ACE2 activity contributes to features of ventricular remodeling associated with the renin-angiotensin system by generating transgenic mice with increased cardiac ACE2 expression. These animals had a high incidence of sudden death that correlated with transgene expression levels. Detailed electrophysiology revealed severe, progressive conduction and rhythm disturbances with sustained ventricular tachycardia and terminal ventricular fibrillation. The gap junction proteins connexin40 and connexin43 were downregulated in the transgenic hearts, indicating that ACE2-mediated gap junction remodeling may account for the observed electrophysiologic disturbances. Spontaneous downregulation of the ACE2 transgene in surviving older animals correlated with restoration of nearly normal conduction, rhythm, and connexin expression.


Subject(s)
Connexins/metabolism , Death, Sudden , Down-Regulation , Heart Block/etiology , Mice, Transgenic , Tachycardia, Ventricular/physiopathology , Angiotensin-Converting Enzyme 2 , Animals , Arrhythmias, Cardiac , Carboxypeptidases/metabolism , Connexin 43/metabolism , Electrocardiography , Electrophysiology , Gene Expression , Gene Expression Regulation, Enzymologic , Heart Block/genetics , Mice , Peptidyl-Dipeptidase A , Tachycardia, Ventricular/metabolism , Transgenes , Ventricular Fibrillation/physiopathology , Gap Junction alpha-5 Protein
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