心血管疾病是造成全世界人口死亡最主要的病因。當心臟受損時，基質細胞蛋白CCN1會在受損組織中表現。CCN1透過結合不同整合素受器可促進血管新生作用，卻也會促進纖維母細胞的凋亡。CCN1在心臟受損中表現所扮演的生理角色仍不清楚，因此本研究進行探討心臟受損時CCN1調控心肌細胞存亡之角色。為測試CCN1在老鼠心臟受損的角色，我們利用基因轉殖老鼠Ccn1dm/dm，其帶有兩序列突變(double mutant; dm) Ccn1基因使CCN1-dm蛋白選擇性無法結合受器整合素α6β1而喪失引發細胞凋亡能力，施以兩種不同心臟損傷的模式，包含(1)異丙基腎上腺素引發心臟過荷的傷害及(2)艾黴素心毒性引發心臟損傷。我們分別給予小鼠異丙基腎上腺素（皮下注射100毫克/公斤/天，連續五天）或者艾黴素（腹腔注射15 毫克/公斤，單一劑量）以引發小鼠心臟受損。在異丙基腎上腺素或艾黴素處理下，Ccn1dm/dm 老鼠對於心臟細胞凋亡或者心肌組織受損有顯著的耐受性，顯示CCN1是一個重要的病理因子，在心臟受刺激時表現進而引發心肌組織受損。藉由一系列初代培養心肌細胞及H9c2心肌母細胞實驗，我們也證實CCN1是藉由與整合素α6β1結合而提高p38促分裂原活化蛋白激酶的活化，進而釋放粒線體中的Smac及HtrA2至細胞質來降低XIAP抑制細胞凋亡作用，使細胞對FasL引發細胞凋亡的感受性增加。綜合以上所述，阻斷CCN1與α6β1的結合可消除小鼠受異丙基腎上腺素及艾黴素引發的相關心肌損傷，顯示CCN1在促進異丙基腎上腺素及艾黴素引發的心毒性扮演重要的角色

Cardiovascular diseases remain a major cause of death worldwide. Upon heart injury, extracellular matrix molecule CCN1 is expressed in damaged tissues. Despite its well-documented pro-angiogenic activities, CCN1 promotes fibroblast apoptosis in some contexts. The physiological role of CCN1 in an injured heart was not clear. We intended to discern how CCN1 may regulate cardiac cell survival during heart injury. To test the role of CCN1 in cardiac injury in mice, we employed two different myocardial injury models, including a work-overload related injury induced by isoproterenol (ISO) and a chemical related injury induced by the chemotherapy agent doxorubicin (DOX). A line of knock-in mice carrying an apoptosis-defective Ccn1 mutant allele, Ccn1-dm, which has disrupted integrin α6β1 binding sites, were tested in the ISO- (100 mg/kg/day subcutaneous injection for 5 days) or DOX (single intraperitoneal injection of 15 mg/kg)-induced cardiac injury. Ccn1dm/dm mice were resistant to both ISO- and DOX-induced cardiac cell apoptosis or myocardial tissue damage, indicating that CCN1 is a critical pathophysiological regulator mediating cardiomyocyte apoptotic death in cardiac injury. We further demonstrated that CCN1 enhanced cellular susceptibility to FasL-induced apoptosis by engaging integrin α6β1 to promote p38 MAPK activation and the release of mitochondrial Smac and HtrA2 to cytosol, thereby counteracting the inhibition of XIAP and facilitating apoptosis using primary neonatal cardiomyocytes and H9c2 cardiomyoblast. In summary, CCN1 is a critical pathophysiological regulator mediating cardiomyocytes apoptotic death upon ISO- and DOX-induced cardiac injury. Disrupting CCN1/α6β1 engagement abolishes ISO- and DOX-associated cardiomyopathy in mice.

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