Shen Yuanjun, Goncharov Dmitry A, Avolio Theodore, Ray Arnab, Okorie Evelyn, DeLisser Horace, Mora Ana L, Vanderpool Rebecca, Kudryashova Tatiana V, Goncharova Elena A
Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Pittsburgh, PA, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Pulm Circ. 2020 Feb 12;10(1):2045894019898593. doi: 10.1177/2045894019898593. eCollection 2020 Jan-Mar.
Pulmonary arterial hypertension (PAH) is a progressive fatal disease with no cure. Inhibition of integrin-linked kinase (ILK) reverses experimental pulmonary hypertension (PH) in male mice, but its effect on severe experimental PH in either male or female animals is unknown. We examined effects of ILK inhibitor Cpd22 on rats with SU5416/hypoxia-induced PH; treatment was performed at six to eight weeks after PH initiation. Five weeks after PH initiation, male and female rats developed similar levels of PH. Eight weeks after PH induction, vehicle-treated male rats had more severe PH than females. Cpd22-treated males, but not females, showed complete suppression of phospho-Akt in small pulmonary arteries (PAs), significantly lower PA medial thickness and percentage of fully occluded arteries, decreased systolic right ventricle (RV) pressure, PA pressure, RV hypertrophy, RV end-diastolic pressure, and improved RV contractility index compared to vehicle-treated group. Cpd22 suppressed proliferation of human male and female PAH pulmonary artery vascular smooth muscle cell (PAVSMC). 17β-estradiol had no effect as a single agent but significantly attenuated Cpd22-dependent inhibition of proliferation in female, but not male, PAH PAVSMC. Taken together, these data demonstrate that male rats develop more severe PH than females but respond better to Cpd22 treatment by reducing pulmonary vascular remodeling, PH, and RV hypertrophy and improving RV functional outcomes. 17β-estradiol diminishes anti-proliferative effect of Cpd22 in female, but not male, human PAH PAVSMC. These findings suggest potential attractiveness of ILK inhibition to reduce established PH in males and suggest that the combination with estrogen-lowering drugs could be considered to maximize anti-proliferative and anti-remodeling effects of ILK inhibitors in females.
肺动脉高压（PAH）是一种无法治愈的进行性致命疾病。抑制整合素连接激酶（ILK）可逆转雄性小鼠的实验性肺动脉高压（PH），但其对雄性或雌性动物严重实验性PH的影响尚不清楚。我们研究了ILK抑制剂Cpd22对SU5416/低氧诱导的PH大鼠的影响；在PH开始后的6至8周进行治疗。PH开始后5周，雄性和雌性大鼠的PH水平相似。PH诱导8周后，接受载体治疗的雄性大鼠的PH比雌性大鼠更严重。与接受载体治疗的组相比，接受Cpd22治疗的雄性大鼠（而非雌性大鼠）的小肺动脉（PA）中磷酸化Akt完全受到抑制，PA中膜厚度和完全闭塞动脉的百分比显著降低，收缩期右心室（RV）压力、PA压力、RV肥大、RV舒张末期压力降低，RV收缩力指数改善。Cpd22抑制了人类雄性和雌性PAH肺动脉血管平滑肌细胞（PAVSMC）的增殖。17β-雌二醇作为单一药物没有效果，但显著减弱了Cpd22对雌性（而非雄性）PAH PAVSMC增殖的依赖性抑制作用。综上所述，这些数据表明，雄性大鼠的PH比雌性大鼠更严重，但通过减少肺血管重塑、PH和RV肥大以及改善RV功能结果，对Cpd22治疗的反应更好。17β-雌二醇减弱了Cpd22对雌性（而非雄性）人类PAH PAVSMC的抗增殖作用。这些发现表明抑制ILK对降低雄性已有的PH具有潜在吸引力，并表明可以考虑与降低雌激素的药物联合使用，以最大化ILK抑制剂对雌性的抗增殖和抗重塑作用。
