血鈣水平與心血管疾病和癌癥關(guān)系的研究進(jìn)展

姚智昇，徐彥貴

(1.天津中醫(yī)藥大學(xué) 研究生院, 天津 300073; 2.天津市第一中心醫(yī)院 藥學(xué)部, 天津 300192)

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短篇綜述

血鈣水平與心血管疾病和癌癥關(guān)系的研究進(jìn)展

姚智昇1，徐彥貴2*

(1.天津中醫(yī)藥大學(xué) 研究生院, 天津 300073; 2.天津市第一中心醫(yī)院 藥學(xué)部, 天津 300192)

血鈣調(diào)節(jié)與許多疾病發(fā)生有一定關(guān)聯(lián)。高血壓及冠心病患者血鈣水平低于健康人群，動(dòng)脈粥樣硬化患者鈣積分大于健康人。不同癌癥血鈣水平呈現(xiàn)不同表現(xiàn)：肺癌、食管癌、胃癌血鈣水平高于健康人；而結(jié)、直腸癌和乳腺癌低于健康人。補(bǔ)充鈣劑可能對(duì)防病治病有一定作用。

血鈣;高血壓;冠心病;癌癥

Ca2+參與肌細(xì)胞收縮、腺細(xì)胞分泌、囊胞中內(nèi)容物釋放、突觸囊胞中遞質(zhì)釋放及某些基質(zhì)蛋白及酶蛋白激活等。Ca2+既是電流的載荷體又起信號(hào)分子作用，其作為第二信使與多種底物蛋白結(jié)合形成結(jié)合蛋白而發(fā)揮作用，本文綜述血鈣水平與心血管疾病及癌癥關(guān)系的新進(jìn)展。

1 血鈣水平與心血管疾病

1.1 高血壓

Ca2+與鈣調(diào)蛋白結(jié)合并激活一氧化氮合酶(NOS),催化生成NO引起血管舒張，有報(bào)道韓國(guó)人高血壓高發(fā)病率與高血漿鈣水平負(fù)相關(guān)(調(diào)整風(fēng)險(xiǎn)比為1.24； 95%置信區(qū)間為1.07～1.43)，且高血鈣水平對(duì)收縮壓影響較舒張壓更顯著[1- 2]。高血壓患者還伴有尿鈣增加[3]，這對(duì)于腎結(jié)石合并高血壓患者采取合理的治療方案具有重要意義。維吾爾族原發(fā)性高血壓患者血鈣水平也低于維吾爾族正常對(duì)照組,且血鈣水平每增加0.2 mmol/L,舒張壓≥90 mmHg(1 mmHg=0.133 kPa) 的危險(xiǎn)性降低0.42[4]，血鈣水平對(duì)血管收縮的影響是通過(guò)Ca2+的調(diào)節(jié)機(jī)制實(shí)現(xiàn)。補(bǔ)充鈣劑可降低高血壓發(fā)病風(fēng)險(xiǎn)[5], 這對(duì)于高血壓患者控制及合理選擇降壓藥物具有重要的意義。

1.2 冠心病

高鈣血癥伴有冠心病的高發(fā)病率，冠狀動(dòng)脈鈣化積分與血清鈣水平明顯相關(guān),血清鈣越高,冠狀動(dòng)脈鈣化積分值越大,鈣化積分值既是冠心病的診斷參數(shù)之一,也是冠心病治療前后的觀察指標(biāo)及篩查隱匿性川崎病[6- 7]。腹部動(dòng)脈鈣化值有助于篩查梗阻性冠狀動(dòng)脈疾病，左心室向心性肥大就暗示有嚴(yán)重的潛在高血壓、冠狀動(dòng)脈鈣化的發(fā)生[8- 9]。頸動(dòng)脈粥樣硬化患者血鈣水平顯著高于健康人群[10]。頸動(dòng)脈粥樣硬化可能是鈣鹽沉積所導(dǎo)致，血鈣水平是影響鈣鹽沉積的先決條件。

1.3 擴(kuò)張型心肌病

嬰兒擴(kuò)張型心肌病伴有嚴(yán)重低血鈣[11]。Ca2+與肌織網(wǎng)上的ryanodine受體結(jié)合,誘發(fā)肌質(zhì)網(wǎng)釋放Ca2+，激活平滑肌上鈣調(diào)蛋白結(jié)合肌球蛋白輕鏈激酶,致肌球蛋白磷酸化和平滑肌收縮。

2 血鈣水平與癌癥

Ca2+作為第二信使參與凋亡早期信號(hào)傳導(dǎo), 破壞內(nèi)環(huán)境穩(wěn)態(tài)可直接引起線粒體釋放色素C等促凋亡因子。腫瘤細(xì)胞無(wú)限增殖和改變細(xì)胞膜受體及離子通道功能表達(dá)的超敏性。而細(xì)胞分裂原誘導(dǎo)Ca2+內(nèi)流,后者使細(xì)胞停止生長(zhǎng)。血鈣不足，降低Ca2+內(nèi)流，減緩對(duì)細(xì)胞生長(zhǎng)抑制。

2.1 肺癌

肺癌患者血鈣水平較健康人增高[12],但伴骨轉(zhuǎn)移肺癌患者與未伴有骨轉(zhuǎn)移患者相比較,血鈣值無(wú)明顯差異。肺癌高鈣血癥發(fā)生率不高,發(fā)生率與骨轉(zhuǎn)移無(wú)關(guān),但臨床中對(duì)于肺癌未伴骨轉(zhuǎn)移患者也應(yīng)警惕高鈣血癥發(fā)生。異硫氰酸烯丙酯刺激肺癌細(xì)胞誘導(dǎo)細(xì)胞內(nèi)Ca2+濃度升高,而TRPA1(一種瞬間受體電位離子通道,激活后引起Ca2+通透入細(xì)胞內(nèi))拮抗劑可抑制Ca2+升高的效應(yīng)[13]。在人類 SPC-AI肺腺癌細(xì)胞系中,通過(guò)L-型鈣通道的Ca2+內(nèi)流被證實(shí)與內(nèi)皮素- 1有關(guān)，促進(jìn)腫瘤增殖。Ca2+的內(nèi)流可能促進(jìn)內(nèi)皮細(xì)胞釋放VEGF/FGE和PDGF,以自分泌和旁分泌方式刺激血管生成。

2.2 乳腺癌

乳腺癌患者血漿中Ca2+、25-羥基維生素D、CaSR及E-cadherin水平均明顯低于乳腺良性腫塊組，提示血鈣、25-羥維生素D、CaSR及E-cadherin與乳腺癌的發(fā)生有密切關(guān)系；原發(fā)性甲狀旁腺功能亢進(jìn)癥和乳腺癌的風(fēng)險(xiǎn)之間的關(guān)聯(lián)的報(bào)告顯示高血鈣的致病作用，而無(wú)甲狀旁腺功能亢進(jìn)癥的高血鈣水平與乳腺癌之間無(wú)關(guān)聯(lián)，并且血鈣水平與乳腺癌腫瘤大小和腫瘤發(fā)展階段無(wú)關(guān)[14- 15]。增強(qiáng)質(zhì)膜Ca2+結(jié)合ATP酶亞型4b的表達(dá)調(diào)節(jié)鈣信號(hào),可能有助于乳腺上皮細(xì)胞正常生長(zhǎng),也有可能誘導(dǎo)其癌變[16]。

2.3 其他癌癥

肝癌細(xì)胞凋亡與Ca2+水平有相關(guān)性，甲基蓮心堿誘導(dǎo)細(xì)胞凋亡期間，提高Ca2+水平均會(huì)增加凋亡蛋白表達(dá)，抑制環(huán)氧合酶- 2活性,達(dá)到治療效果[17]。結(jié)、直腸癌患者血鈣值低于健康人[18],每天攝入鈣低于500 mg年輕婦女結(jié)直腸癌風(fēng)險(xiǎn)增加。補(bǔ)充鈣提示可能預(yù)防腸癌。血清每增加0.1 mmol/L Ca2+，卵巢癌致命風(fēng)險(xiǎn)增高52%，如果是電離血清則會(huì)增高144%[19]。對(duì)化療藥物缺乏敏感性的癌細(xì)胞,Ca2+濃度呈現(xiàn)較高水平[20],Ca2+濃度升高可能與細(xì)胞自身侵襲性增加有關(guān)，血鈣水平對(duì)化療效果可能會(huì)有一定的協(xié)同作用。對(duì)于腎細(xì)胞癌高發(fā)性骨轉(zhuǎn)移伴隨著骨組織Ca2+濃度增高[21]。食管癌和胃癌血鈣水平高于健康人，降低鈣結(jié)合蛋白S100A14，胃癌腫瘤細(xì)胞未分化和不良預(yù)后增加[22- 23]。

T-型鈣通道作為癌癥治療新途徑[24]。在癌細(xì)胞中T-型鈣通道異常表達(dá)或釋放頻繁發(fā)生，供給癌細(xì)胞增殖，對(duì)抗癌癥治療，T型鈣通有可能作為治療癌癥的分子靶點(diǎn)，這為開(kāi)發(fā)抗癌藥物提供了新方向。此外，腫瘤細(xì)胞轉(zhuǎn)移與細(xì)胞局部張力有關(guān),張力激活鈣通道是局部張力轉(zhuǎn)化為鈣信號(hào)的傳導(dǎo)器。補(bǔ)充鈣不能改善結(jié)、直腸癌和乳腺癌的治病風(fēng)險(xiǎn)和病死率，但可以降低前列腺癌的致病風(fēng)險(xiǎn)[25]。補(bǔ)充鈣對(duì)其他癌癥的影響還待進(jìn)一步研究。

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Progress on the serum calcium level with cardiovascular disease and cancer

YAO Zhi-sheng1, XU Yan-gui2*

(1.Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300073;2.Dept. of Pharmacy,Tianjin First Central Hospital, Tianjin 300192,China)

Calcium regulation has some relationship with disease.The serum calcium level of patients with coronary heart disease and hypertension are lower that of than the healthy people. The calcium score of atherosclerosis is greater than healthy people. Different cancers show different performance levels of calcium: lung cancer, esophageal cancer and gastric cancer serum calcium levels higher than the healthy people; while the colorectal cancer and breast cancer is lower than that of healthy people. Taking calcium supplements may be helpful for some of diseases prevention and cure.

blood calcium; hypertension; coronary heart disease; cancer

2014- 09- 25

2015- 01- 22

1001-6325(2015)06-0851-03

R- 1

A

*通信作者(corresponding author)：13920455619@139.com