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Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk.

ABSTRACT: Angiotensin-converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk.The purpose of this study was to investigate whether genetic variations in ACE-related pathways are associated with SCA risk. Because these pathways are sex dependent and are influenced by estrogen, we examined these genotype-SCA associations in the full study population and tested for interaction with gender.In a population-based case-control study set in King County, Washington, 211 SCA cases (80% male; mean age 59 years,) and 730 age- and gender-matched controls of European descent were genotyped for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). The association of SNPs and haplotypes with SCA risk was examined using logistic regression.AGTR1 SNP rs1492099 (allele frequency 15%) was associated with decreased SCA risk (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.4-0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test P = .001), with haplotype 2 (allele frequency 27%) associated with increased risk (OR 1.26, 95% CI 1.1-1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction P value range 0.0004-0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency 42%) was associated with decreased risk (OR 0.44, 95% CI 0.3-0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction.Variations in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. These study findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk.

SUBMITTER: Sotoodehnia N

PROVIDER: S-EPMC2757102 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk.

Sotoodehnia Nona N Li Guo G Johnson Catherine O CO Lemaitre Rozenn N RN Rice Kenneth M KM Rea Thomas D TD Siscovick David S DS

Heart rhythm 20090609 9

<h4>Background</h4>Angiotensin-converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk.<h4>Objective</h4>The purpose of this study was to investigate whether genetic variations in ACE-related pathways are associated with SCA risk. Because these pathways are sex dependent and are influenced by estrogen, we examined these genotype-SCA associations in the full study population and tested for interaction with gender.<h4>Methods</h4>In a population-based ca ...[more]

PMID: 19716087

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Project description:Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+) current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.

Project description:Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.

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Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk.

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Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk.

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