Cardiac overexpression of metallothionein rescues cold exposure-induced myocardial contractile dysfunction through attenuation of cardiac fibrosis despite cardiomyocyte mechanical anomalies

详细信息    查看全文

• 作者：Yingmei Zhang ; Nan Hu ; Yinan Hua ; Kacy L. Richmond ; Feng Dong ; Jun Ren
• 关键词：Cold exposure ; Metallothionein ; Contraction ; Reactive oxygen species ; Fibrosis ; Apoptosis ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 出版时间：15 July, 2012
• 年：2012
• 卷：53
• 期：2
• 页码：194-207
• 全文大小：1273 K

文摘

Cold exposure is associated with an increased prevalence of cardiovascular disease although the mechanism is unknown. Metallothionein, a heavy-metal-scavenging antioxidant, protects against cardiac anomalies. This study was designed to examine the impact of metallothionein on cold exposure-induced myocardial dysfunction, intracellular Ca²⁺ derangement, fibrosis, endoplasmic reticulum (ER) stress, and apoptosis. Echocardiography, cardiomyocyte function, and Masson trichrome staining were evaluated in Friend virus B (FVB) and cardiac-specific metallothionein transgenic mice after cold exposure (3 months, 4 ¡ãC). Cold exposure increased plasma levels of norepinephrine, endothelin-1, and TGF-¦Â; reduced plasma NO levels and cardiac antioxidant capacity; enlarged ventricular end-systolic diameter; compromised fractional shortening; promoted reactive oxygen species (ROS) production and apoptosis; and suppressed the ER stress markers Bip, calregulin, and phospho-eIF2¦Á, accompanied by cardiac fibrosis and elevated levels of matrix metalloproteinases and Smad-2/3 in FVB mice. Cold exposure-induced echocardiographic, histological, ER stress, ROS, apoptotic, and fibrotic signaling changes (but not plasma markers) were greatly improved by metallothionein. In vitro metallothionein induction by zinc chloride ablated H₂O₂- but not TGF-¦Â-induced cell proliferation in fibroblasts. In summary, our data suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of myocardial fibrosis.