Abstract 561: Smad1 Signaling Is Essential For The Adult Heart And In Protecting The Myocardium To Ischemia/reperfusion Injury
Background: Smad1 signaling is essential for cardiovascular development. It was previously reported that cardiac specific Smad1 overexpression results in a myocardio-protective effect in myocardial ischemia/reperfusion (I/R). However, it remains unclear if Smad1 signaling is required for an adult heart.
Methods and results: To investigate a role of Smad1 signaling in cardiac pathophysiology, we generated a cardiomyocyte-restricted Smad1 knockout line (CS1K) using Cre-loxP technology. A previously published mouse line with cardiomyocyte-restricted Cre overexpression (α-MyHC-Cre) was used for the crossing and as control. Smad1 was largely eliminated in cardiomyocytes isolated from CS1K mice. The CS1K mice were overtly normal during the first 5– 6 months after birth. No pathophysiological abnormality could be detected during this period of time. However, the CS1K mice manifested cardiac hypertrophy at around 6 months and heart failure at later time points. Heart weight to body weight ratio of 8–10 month CS1K mice was substantially increased compared with controls (8.7 vs 4.5, n=12 and 8, P<0.01). The one year survival rate for CS1K mice was decreased by 65% compared with controls (n=31, P<0.01). To investigate the effect of Smad1 deficiency in cardiomyocytes in response to myocardial injuries, the CS1K and control mice at the ages of 2–3 months were subjected to an in vivo I/R with occlusion of the left anterior descending artery (30 min) followed by reperfusion (24 hours). Echocardiography assessment revealed no functional difference before I/R between CS1K mice and controls. However, the infarct size was significantly larger in CS1K mice as compared to controls (46.5±9.1% vs. 20.2±3.4%, n=9, p<0.05) and these larger infarctions were associated with a significant increase in a panel of serum cytokines (IL-6, MCP-1, TNFα and TGF-b1, n=9, P<0.01).
In conclusion: Together, these data point towards an essential role for Smad1 in the heart at baseline and in protecting against various injuries.