Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner.
Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner.
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DOI：
10.1016/j.yjmcc.2011.10.021
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发表时间：
2012-01
影响因子：
5
通讯作者：
Caron KM
中科院分区：
文献类型：
--
作者：
Barrick CJ;Lenhart PM;Dackor RT;Nagle E;Caron KM
在高血压患者的肥厚反应、心脏重塑和向心力衰竭的转变中存在性别差异，虽然其中一些差异可能受到雌激素的影响，但影响心脏保护的雌激素下游遗传途径尚未完全阐明。我们先前已经表明，肾上腺髓质素（AM）的心脏保护作用，心血管疾病严重程度的新兴临床生物标志物，在小鼠模型中随性别而变化。心血管应激过程中的AM信号通过与G蛋白偶联受体降钙素受体样受体（CGRP）的相互作用受到受体活性修饰蛋白3（RAMP 3）的强烈调节。与AM一样，RAMP 3的表达也受到雌激素的有效调节，因此我们试图确定遗传性Ramp 3缺失对心脏适应慢性高血压的影响，特别关注潜在的性别差异。我们产生RAMP 3 −/−小鼠，并将其与RenTgMK小鼠进行繁殖，这些小鼠始终表现出严重的血管紧张素II介导的CV疾病，并将RenTgMK与RenTgMK：RAMP 3 −/−后代的CV疾病进展进行比较。正如预期的那样，RAMP 3基因表达在RenTgMK小鼠的心血管组织中更高，并且相对于野生型对照，在雌性RenTgMK小鼠中更强烈地上调。RAMP 3丢失不影响高血压的发展或左心室（LV）中血管周围和间质纤维化的存在和严重程度。然而，超声心动图显示，虽然RenTgMK小鼠出现了持续收缩功能的向心性心脏肥大，但雄性RenTgMK：RAMP 3 −/−小鼠显示出LV腔扩张和收缩功能下降的证据，提示心脏失代偿。与心力衰竭的这些指标一致，雄性RenTgMK：RAMP 3 −/−小鼠的心脏凋亡增加，Akt活化升高。这些表型在雌性RenTgMK：RAMP 3 −/−小鼠中不存在。总的来说，这些数据证明了RAMP 3在慢性高血压背景下的性别依赖性心脏保护作用。
Sex differences exist in the hypertrophic response, cardiac remodeling, and transition to heart failure of hypertensive patients, and while some of these differences are likely influenced by estrogen, the genetic pathways downstream of estrogen that impact on cardioprotection have yet to be fully elucidated. We have previously shown that the cardioprotective effects of adrenomedullin (AM), an emerging clinical biomarker for cardiovascular disease severity, vary with sex in mouse models. AM signaling during cardiovascular stress is strongly modulated by receptor activity-modifying protein 3 (RAMP3) via its interaction with the G protein-coupled receptor calcitonin receptor-like receptor (CLR). Like AM, RAMP3 expression is potently regulated by estrogen, and so we sought to determine the consequences of genetic Ramp3 loss on cardiac adaptation to chronic hypertension, with a particular focus on characterizing potential sex differences. We generated and bred RAMP3−/− mice to RenTgMK mice that consistently display severe angiotensin II-mediated CV disease and compared CV disease progression in RenTgMK to that of RenTgMK:RAMP3−/− offspring. As expected, RAMP3 gene expression was higher in cardiovascular tissues of RenTgMK mice and more strongly up-regulated in female RenTgMK mice relative to wildtype controls. RAMP3 loss did not affect the development of hypertension or the presence and severity of perivascular and interstitial fibrosis in the left ventricle (LV). However, echocardiography revealed that while RenTgMK mice developed concentric cardiac hypertrophy with sustained systolic function, male RenTgMK:RAMP3−/− mice showed evidence of LV chamber dilatation and depressed systolic function, suggestive of cardiac decompensation. Consistent with these measures of heart failure, male RenTgMK:RAMP3−/− mice had increased cardiac apoptosis and elevated activation of Akt. These phenotypes were not present in female RenTgMK:RAMP3−/− mice. Collectively, these data demonstrate a sex-dependant, cardioprotective role of RAMP3 in the setting of chronic hypertension.
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DOI：
10.1152/ajpheart.00953.2007
发表时间：
2008-06-01
影响因子：
4.8
作者：
DeMarco, Vincent G.;Habibi, Javad;Dellsperger, Kevin C.
通讯作者：
Dellsperger, Kevin C.
影响因子：
4.8
作者：
Bomberger, JM;Spielman, WS;Parameswaran, N
通讯作者：
Parameswaran, N
影响因子：
--
作者：
Hewitt, SC;Collins, J;Korach, KS
通讯作者：
Korach, KS
影响因子：
4.1
作者：
Husmann, K;Sexton, PM;Born, W
通讯作者：
Born, W
DOI：
10.1016/s0006-291x(02)00487-4
发表时间：
2002-06-07
影响因子：
3.1
作者：
Cueille, C;Pidoux, E;Garel, JM
通讯作者：
Garel, JM