Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction
Rationale: Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post-MI and to identify the processes that initiate transition to maladaptive remodeling is of major clinical interest.
Objective: To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI.
Methods and Results: Titin properties were analyzed in Langendorff-perfused mouse hearts after 20' ischemia / 60' reperfusion (I/R) and mouse hearts that underwent ligature of the left anterior descending coronary artery (LAD) for 3 or 10 days. Cardiac myocyte passive tension (PT) was significantly increased one hour after I/R as well as 3 and 10 days after LAD-ligature. The increased PT was caused by hypophosphorylation of the N2-Bus and hyperphosphorylation of the PEVK-region of titin. Blocking of interleukine-6 (IL-6) prior to LAD-ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine IL-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin proteasome system.
Conclusions: We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by IL-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.
- passive tension
- posttranslational modification
- protein turnover
- sarcomere physiology
- myocardial infarction
- remodeling heart failure
- Received August 1, 2016.
- Revision received September 7, 2016.
- Accepted September 15, 2016.