Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females.
Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females.
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DOI：
10.3389/fcvm.2021.757784
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发表时间：
2021
影响因子：
3.6
通讯作者：
Fairweather D
中科院分区：
文献类型：
--
作者：
Norton N;Bruno KA;Di Florio DN;Whelan ER;Hill AR;Morales-Lara AC;Mease AA;Sousou JM;Malavet JA;Dorn LE;Salomon GR;Macomb LP;Khatib S;Anastasiadis ZP;Necela BM;McGuire MM;Giresi PG;Kotha A;Beetler DJ;Weil RM;Landolfo CK;Fairweather D
背景：阿霉素是一种广泛使用且有效的化疗药物，但主要的限制性副作用是心肌病，在某些患者中会导致充血性心力衰竭。 TRPC6 的遗传变异与阿霉素诱导的心脏毒性的发生有关，表明 TRPC6 可能是癌症患者心脏保护的治疗靶点。方法：在雄性和雌性 B6.129 和 Trpc6 敲除小鼠中评估 Trpc6 缺乏对预防阿霉素诱导的心脏损伤和功能的影响。小鼠每隔一天腹腔注射阿霉素，共注射 6 次（4 mg/kg/剂，累积剂量 24 mg/kg）。在心脏切片中通过空泡化和纤维化的量化来测量心脏损伤，在心脏组织中通过 Tnni3 和 Myh7 的基因表达来测量心脏损伤。通过超声心动图测定心脏功能。结果：当用阿霉素治疗时，与野生型对照相比，Trpc6 缺陷的雄性小鼠的心脏损伤标志物有所改善，空泡、纤维化和 Myh7 表达显着减少，Tnni3 表达增加。同样，用多柔比星治疗的雄性 Trpc6 缺陷小鼠的 LVEF、缩短分数、心输出量和每搏输出量有所改善。与雄性小鼠相比，雌性小鼠对阿霉素引起的心脏损伤和功能变化的敏感性较低，但 Trpc6 缺陷的雌性小鼠在阿霉素治疗下改善了空泡形成。在野生型和 Trpc6 缺陷型小鼠中观察到体重以及对阿霉素反应的 Trpc1、Trpc3 和 Rcan1 表达方面的性别差异。结论：Trpc6 会促进雄性小鼠阿霉素治疗后的心脏损伤，导致心肌病。雌性小鼠对心脏毒性的敏感性较低，调节其他 Trpc 通道和 Rcan1 表达的能力更强。
Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients. Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7. Cardiac function was determined by echocardiography. Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin. Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.
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影响因子：
5.6
作者：
Chinigò G;Fiorio Pla A;Gkika D
通讯作者：
Gkika D
影响因子：
4.6
作者：
Kitajima N;Numaga-Tomita T;Watanabe M;Kuroda T;Nishimura A;Miyano K;Yasuda S;Kuwahara K;Sato Y;Ide T;Birnbaumer L;Sumimoto H;Mori Y;Nishida M
通讯作者：
Nishida M
DOI：
10.33594/000000131
发表时间：
2019-01-01
期刊：
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
影响因子：
--
作者：
Kalidhindi, Rama Satyanarayana Raju;Katragadda, Rathnavali;Sathish, Venkatachalem
通讯作者：
Sathish, Venkatachalem
影响因子：
5.4
作者：
Coronado, Michael J.;Bruno, Katelyn A.;Fairweather, DeLisa
通讯作者：
Fairweather, DeLisa
影响因子：
5.3
作者：
Dietrich, A;Schnitzler, MMY;Birnbaumer, L
通讯作者：
Birnbaumer, L