Yang Liming, Quan Shuo, Nasjletti Alberto, Laniado-Schwartzman Michal, Abraham Nader G
Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
Hypertension. 2004 Jun;43(6):1221-6. doi: 10.1161/01.HYP.0000126287.62060.e6.
The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of approximately 5x10(9) cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16+/-3, 27+/-3, and 38+/-3 at 0.5, 2, and 10 ng) was surpassed (P<0.05) in LXSN rats (23+/-1, 37+/-2, and 52+/-2 at 0.5, 2, and 10 ng). Importantly, treating LSN-HHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli.
血红素-血红素加氧酶（HO）系统与血管反应性和血压的调节有关。本研究探讨了HO过表达会降低对血管紧张素II（Ang II）的升压反应性这一观点。5日龄的Sprague-Dawley大鼠接受左心室内注射约5×10⁹ cfu/mL含有人HO-1正义链（LSN-HHO-1）、大鼠HO-1反义链（LSN-RHO-1-AS）或对照逆转录病毒（LXSN）的逆转录病毒。三个月后，分别给大鼠植入股动脉和静脉导管，用于测定平均动脉压（MAP）和给予Ang II。注射LSN-HHO-1而非LXSN的大鼠在多个组织中表达人HO-1 mRNA和蛋白。在表达和不表达人HO-1的大鼠中，给予Ang II后血压均升高。然而，LSN-HHO-1大鼠（在0.5、2和10 ng时分别为16±3、27±3和38±3 mmHg）的Ang II诱导的升压反应在LXSN大鼠（在0.5、2和10 ng时分别为23±1、37±2和52±2 mmHg）中被超过（P<0.05）。重要的是，用HO抑制剂中卟啉锡（SnMP）处理LSN-HHO-1大鼠可增强（P<0.05）Ang II诱导的升压反应，使其达到与LXSN大鼠中观察到的水平无差异。与注射LXSN的大鼠相比，注射LSN-RHO-1-AS的大鼠肾HO-1蛋白表达和HO活性相对于对照LXSN大鼠有所降低。给予Ang II（0.1至2 ng）使注射LSN-RHO-1-AS的大鼠的MAP出现小幅度（4至5 mmHg）但显著的升高（P<0.05）。这些数据表明，HO-1的过表达导致对Ang II的升压反应性降低，这很可能是由于HO-1产物（可能是CO）生成增加，其具有抑制血管对收缩刺激的反应性的能力。
