Effent Of Survivin Expression In Hypoxic Huaman Pulmonary Arterial Smooth Muscle Cells On The Apoptosis And Proliferation

Hypoxic pulmonary hypertension(HPH) is a frequent disease characterized by increased pulmonary arterial pressure and adverse remodeling of pulmonary arteries(PAs), leading to right ventricular failure and premature death. Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells(PASMCs) are widely accepted as one of the main causes of PAs remodeling during hypoxia. Most current therapies for pulmonary hypertension(PH) focus on dilating the PAs and lack of specificity to the pulmonary circulation. However, such treatments do not address what appears to be a key underlying cause, namely the presence of excessively proliferative and apoptosis-resistant PASMCs. Therapies with the capacity to inhibit the proliferation of PASMCs or promote apoptosis of these cells may be effective to this end.Cancer cells and PASMCs have many similarities. For example, both are lock in apoptosis-resistant states. Survivin, a member of the inhibitor of apoptosis(IAP) protein gene family that negatively regulating programmed cell death, is well documented to be overexpressed in essentially all human cancers. Survivin regulates two essential cellular processes, i.e., it inhibits apoptosis and promotes cell proliferation. Recent studies show that survivin regulates pulmonary artery smooth muscle cell proliferation, which keeps on a high level expression in media of pulmonary artery from pulmonary hypertension. Our previous study found survivin is expressed in the media of the distal PAs of rats with chronic hypoxia induced PH.The present study aimed to investigate the effect of survivin expression in hypoxic human PASMCs(HPASMCs) on the apoptosis and proliferation and therapeutic potential of YM155, a selected survivin suppressant, on hypoxic HPASMCs. HPASMCs were divided randomly into 6 groups: ①Normoxia(N group):cultured under normoxia; ②Normoxia+YM155(NY group):cultured under normoxia with YM155, a selective survivin inhibitor, for 24 h; ③Hypoxia(H group):cultured under hypoxia for 24 h; ④Hypoxia+1nmol/L YM155(HY1 group):cultured under hypoxia with 1nmol/L YM155 for 24 h; ⑤Hypoxia+10nmol/L YM155(HY10 group):cultured under hypoxia with 10nmol/L YM155 for 24 h; ⑥Hypoxia+100nmol/L YM155(HY100 group):cultured under hypoxia with 100nmol/L YM155 for 24 h.The m RNA and protein expressions of survivin were measured by real time PCR and Western Blot respectively. Cell proliferation was determined using a Cell Counting Kit-8(CCK-8). Apoptosis was detected with a TUNEL test.The mRNA and protein expressions of survivin were observed in the H group(17086±1044, 0.837±0.027), but not in N group(1, 0.016±0.06). The cell proliferation in H group(1.438±0.121) was significantly increased compared with N group(0.988±0.071, q= 6.484, P<0.05). The apoptosis in H group(0.612±0.500) was significantly decreased compared with N group(2.683±1.360, q=3.532, P<0.05). As compared with H group, the survivin m RNA, survivin protein and cell proliferation in hypoxia plus 1n M, 10 n M,100 n M YM155 groups(8074±2135, 5614±709, 1382±347, 0.382±0.041, 0.281±0.025, 0.021±0.002, 1.318±0.067, 1.168±0.071, 0.845±0.129, q=8.59, 11.14, 15.53, 20.26, 24.77, 36.36, 2.581, 3.980, 8.733, all P<0.05) significant decreased, and apoptosis in hypoxia plus 1n M, 10 n M,100 n M YM155 groups(5.517±1.711, 6.658±1.487, 7.972±1.934, q=6.014, 7.413, 9.023, all P<0.05) enhanced in a dose-dependent manner.In conclusion, the present study revealed that survivin protein and m RNA were expressed in HPASMCs, during hypoxia. We found that YM155, known as a selective srvivin inhibitor, promotes apoptosis and ameliorates proliferation in HPASMCs. Thus, survivin may act as a critical role in the development and progression of hypoxic PAs remodeling and PH.