Fang Qiujuan, Kan Hong, Lewis William, Chen Fangping, Sharma Puneet, Finkel Mitchell S
Department of Medicine, WVU Cardiology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Medical Center Drive, Morgantown, WV 26506-9157, USA.
Cardiovasc Toxicol. 2009 Mar;9(1):39-45. doi: 10.1007/s12012-009-9035-5. Epub 2009 Apr 1.
Mechanisms responsible for HIV cardiomyopathy are unknown, but may include direct effects of HIV proteins on the heart. Transgenic mice (TG) expressing HIV Tat protein targeted to the myocardium, +/- Tat TG, have revealed anatomical and biochemical defects in the heart. The present studies were conducted to clarify the effect of Tat on cardiac function. In vivo hemodynamics was measured in awake mice after inserting a catheter tip in the left ventricle under general anesthesia. Under the age of 3 months, the heart rate (HR) was significantly lower in TG (591 +/- 47 vs. 716 +/- 45 bpm, TG versus FVB control (FVB), respectively (P < 0.05; n = 8-12). Other hemodynamic indexes, including left ventricular systolic pressure (LVSP), positive and negative dp/dt (mmHg/s), and left ventricular end diastolic pressure (LVEDP) remained indistinguishable from FVB. At 6 months, however, ventricular dysfunction was evident in TG (HR = 580 +/- 47 vs. 673 +/- 25 bpm, TG versus FVB, P < 0.05); LVSP (132 +/- 6 vs. 147 +/- 6 mmHg, TG versus FVB; P < 0.05); LVEDP (15 +/- 4 vs. 8 +/- 6 mmHg, TG vs. FVB, P < 0.05); +dp/dt = 8872 +/- 331 vs. 10026 +/- 796 mmHg/s TG versus FVB, P < 0.01) and -dp/dt (7403 +/- 432 vs. 8835 +/- 368 mmHg/s, TG versus FVB, P < 0.01; n = 8-12, in each group). The change in percentage of fractional shortening in response to isoproterenol was also significantly reduced in cardiac myocytes isolated from TG versus FVB (P < 0.05). Thus, targeted myocardial transgenic expression of HIV Tat in mice results in relative bradycardia, depression in systolic and diastolic functions in vivo, and blunted adrenergic responsiveness in vitro.
导致HIV心肌病的机制尚不清楚，但可能包括HIV蛋白对心脏的直接作用。表达靶向心肌的HIV Tat蛋白的转基因小鼠（TG），即±Tat TG，已揭示出心脏存在解剖学和生化缺陷。进行本研究以阐明Tat对心脏功能的影响。在全身麻醉下将导管尖端插入左心室后，对清醒小鼠进行体内血流动力学测量。在3个月龄以下时，TG的心率（HR）显著低于对照组（分别为591±47次/分钟和716±45次/分钟，TG组与FVB对照组（FVB）相比，P<0.05；n = 8 - 12）。其他血流动力学指标，包括左心室收缩压（LVSP）、正负dp/dt（mmHg/s）和左心室舒张末期压力（LVEDP）与FVB组无显著差异。然而，在6个月时，TG出现明显的心室功能障碍（HR = 580±47次/分钟与673±25次/分钟，TG组与FVB组相比，P<0.05）；LVSP（132±6 mmHg与147±6 mmHg，TG组与FVB组相比，P<0.05）；LVEDP（15±4 mmHg与8±6 mmHg，TG组与FVB组相比，P<0.05）；+dp/dt = 8872±331 mmHg/s与10026±796 mmHg/s，TG组与FVB组相比，P<0.01）以及 -dp/dt（7403±432 mmHg/s与8835±368 mmHg/s，TG组与FVB组相比，P<0.01；每组n = 8 - 12）。与FVB组相比，从TG分离的心肌细胞对异丙肾上腺素反应时的缩短分数百分比变化也显著降低（P<0.05）。因此，小鼠心肌靶向转基因表达HIV Tat会导致相对心动过缓、体内收缩和舒张功能降低以及体外肾上腺素能反应迟钝。
