Brooks W W, Bing O H, Conrad C H, O'Neill L, Crow M T, Lakatta E G, Dostal D E, Baker K M, Boluyt M O
Department of Veterans Affairs Medical Center, Department of Medicine, Boston University School of Medicine, Mass 02130, USA.
Hypertension. 1997 Dec;30(6):1362-8. doi: 10.1161/01.hyp.30.6.1362.
The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.
自发性高血压大鼠（SHR）在平均21月龄时会从稳定的代偿性左心室（LV）肥厚转变为心力衰竭（HF），其特征是α-肌球蛋白重链（α-MHC）基因表达降低，心房利钠因子（ANF）、前α1（III）胶原蛋白和转化生长因子β1（TGF-β1）基因表达增加。我们检验了以下假设：在SHR中，分别在HF发作之前和之后给予血管紧张素转换酶抑制剂（ACEI），将预防和逆转与HF相关的基因表达变化。我们还研究了ACEI对肾素-血管紧张素系统循环和心脏成分的影响。在12、18和21月龄时，对无HF的SHR和有HF的SHR开始给予ACEI（饮水中卡托普利2 g/L）。将结果与年龄匹配的正常血压Wistar-Kyoto（WKY）大鼠以及未治疗的有和无HF证据的SHR的结果进行比较。在HF发作之前开始给予ACEI可预防与向HF转变相关的α-MHC、ANF、前α1（III）胶原蛋白和TGF-β1基因表达的变化。在HF发作之后开始给予ACEI可使TGF-β1 mRNA水平降低50%（P<0.05），并使α-MHC mRNA水平升高2至3倍（P<0.05）。ACEI使肾素和血管紧张素I的循环水平升高4至6倍，但令人惊讶的是，血管紧张素II的血浆水平并未降低。ACEI使WKY和SHR的左心室肾素mRNA水平升高2至3倍，但不影响左心室血管紧张素原mRNA水平。结果表明，ACEI对SHR的抗HF益处可能至少部分是通过对特定基因表达的影响介导的，这些基因包括编码α-MHC、ANF、TGF-β1、前α1（III）胶原蛋白和肾素-血管紧张素系统成分的基因。
