All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system
All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system
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DOI：
10.1152/ajpheart.01301.2007
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Pan, Jing
中科院分区：
文献类型：
--
作者：
Choudhary, Rashmi;Palm-Leis, Ants;Pan, Jing
本研究旨在探讨全反式维甲酸（RA）对压力超负荷大鼠心脏重构的影响。对雄性Sprague-Dawley大鼠进行假手术和主动脉缩窄手术。假手术对照组和主动脉缩窄组大鼠在手术后用RA治疗5个月。压力超负荷大鼠表现出显著增加的间质和血管周围纤维化，心脏重量与体重的比值，心钠素和脑钠素的基因表达。超声心动图分析显示，压力超负荷引起收缩和舒张功能障碍，表现为缩短分数、射血分数、每搏输出量降低，E/E a比值和等容舒张时间增加。RA治疗可预防压力超负荷大鼠心脏结构和功能的上述改变以及肥厚基因的表达。RA恢复Bcl-2/Bax比值，抑制caspase-3和-9的裂解，阻止SOD-1和SOD-2水平的下降。RA通过上调丝裂原活化蛋白激酶磷酸酶（MKP）-1和MKP-2抑制压力过载诱导的ERK 1/2、JNK和p38磷酸化。RA通过上调血管紧张素转换酶（ACE）2的表达和抑制心脏和肾脏的肾素、血管紧张素原、ACE和血管紧张素1型受体的表达来抑制压力超负荷诱导的血管紧张素II的产生。在培养的新生心肌细胞中观察到类似的结果，以响应静态拉伸。这些结果表明，RA通过抑制肾素-血管紧张素系统组分的表达，对压力超负荷诱导的心脏重构具有显著的抑制作用。
This study was designed to determine the effect of all-trans retinoic acid (RA) on the development of cardiac remodeling in a pressure overload rat model. Male Sprague-Dawley rats were subjected to sham operation and the aortic constriction procedure. A subgroup of sham control and aortic constricted rats were treated with RA for 5 mo after surgery. Pressure-overloaded rats showed significantly increased interstitial and perivascular fibrosis, heart weight-to-body weight ratio, and gene expression of atrial natriuretic peptide and brain natriuretic peptide. Echocardiographic analysis showed that pressure overload induced systolic and diastolic dysfunction, as evidenced by decreased fractional shortening, ejection fraction, stroke volume, and increased E-to-E-a ratio and isovolumic relaxation time. RA treatment prevented the above changes in cardiac structure and function and hypertrophic gene expression in pressure-overloaded rats. RA restored the ratio of Bcl-2 to Bax, inhibited cleavage of caspase-3 and -9, and prevented the decreases in the levels of SOD-1 and SOD-2. Pressure overload-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by RA, via upregulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2. The pressure overload-induced production of angiotensin II was inhibited by RA via upregulation of expression of angiotensin-converting enzyme (ACE)2 and through inhibition of the expression of cardiac and renal renin, angiotensinogen, ACE, and angiotensin type 1 receptor. Similar results were observed in cultured neonatal cardiomyocytes in response to static stretch. These results demonstrate that RA has a significant inhibitory effect on pressure overload-induced cardiac remodeling, through inhibition of the expression of renin-angiotensin system components.