Li Z, Bing O H, Long X, Robinson K G, Lakatta E G
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Am J Physiol. 1997 May;272(5 Pt 2):H2313-9. doi: 10.1152/ajpheart.1997.272.5.H2313.
The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca(2+)-activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quantified in cross sections of myocardium by the terminal deoxynucleotidyltransferase- mediated 2'-deoxyuridine 5'-triphosphate nick end labeling technique. To identify the type of the cells undergoing apoptosis, sections were also stained for alpha-sarcomeric actin. Apoptotic cells were significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3.98 cells/100,000 nuclei in SHR-NF; P < 0.05 and vs. 2.21 +/- 1.4 cells/100,000 nuclei in WKY; P < 0.01). Captopril treatment of SHR-F reduced the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P < 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expressed by hearts among the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apoptotic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhibitor captopril, which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies heart failure.
高龄自发性高血压大鼠（SHR）从代偿性肥大转变为心力衰竭，与胶原蛋白显著增加、心肌细胞质量减少以及最大钙激活肌原纤维力降低有关。我们推测，心肌细胞质量减少及相关功能丧失可能是由于凋亡导致细胞死亡增加所致。为验证这一假设，我们研究了衰竭的SHR（SHR - F）和未衰竭的SHR（SHR - NF）以及年龄匹配的Wistar - Kyoto大鼠（WKY）的心脏。此外，还研究了平均用血管紧张素转换酶抑制剂（卡托普利）治疗27天的SHR - F的心脏。通过末端脱氧核苷酸转移酶介导的2'-脱氧尿苷5'-三磷酸缺口末端标记技术对心肌横切面中的凋亡细胞进行定量。为确定发生凋亡的细胞类型，切片还进行了α - 肌动蛋白染色。SHR - F中的凋亡细胞显著增加（SHR - NF中为8.05±3.98个细胞/100,000个细胞核，SHR - F中为38.92±12.79个细胞/100,000个细胞核；P < 0.05，与WKY中2.21±1.4个细胞/100,000个细胞核相比，P < 0.01）。卡托普利治疗SHR - F可使凋亡细胞数量降至SHR - NF的水平（9.17±1.53个细胞/100,000个细胞核；与SHR - F相比，P < 0.01）。大多数凋亡细胞源自心肌细胞。三组心脏中Bcl - 2蛋白表达无显著差异。与WKY相比，两个SHR组中的WAF - 1 mRNA水平均升高；在SHR - F中，WAF - 1 mRNA密度高于SHR - NF。因此，衰竭的SHR心脏中凋亡细胞数量增加，提示在该模型中，从稳定代偿转变为心力衰竭过程中，凋亡可能是参与心肌细胞质量减少的一种机制。给予血管紧张素转换酶抑制剂卡托普利可改善该模型中的心力衰竭，且与心力衰竭时过度的凋亡减少有关。
