Author + information
- Received July 20, 2017
- Revision received July 24, 2017
- Accepted July 31, 2017
- Published online September 18, 2017.
- Lei Song, MD,
- Lai Wang, MD,
- Fuqiang Li, PhD,
- Ada Yukht, MS,
- Minghui Qin, PhD,
- Haley Ruther, MS,
- Mingjie Yang, PhD,
- Aurelio Chaux, MD,
- Prediman K. Shah, MD and
- Behrooz G. Sharifi, PhD∗ ()
- ↵∗Address for correspondence:
Dr. Behrooz G. Sharifi, Oppenheimer Atherosclerosis Research Center, Division of Cardiology, Cedar-Sinai Heart Institute, Cedar-Sinai Medical Center, 8700 Beverly Boulevard, Davis Building #1016, Los Angeles, California 90048.
Background Tenascin-C (TNC) is a highly conserved matricellular protein with a distinct expression pattern during development and disease. Remodeling of the left ventricle (LV) in response to pressure overload leads to the re-expression of the fetal gene program.
Objectives The aim of this study was to investigate the function of TNC in cardiac hypertrophy in response to pressure overload.
Methods Pressure overload was induced in TNC knockout and wild-type mice by constricting their abdominal aorta or by infusion of angiotensin II. Echocardiography, immunostaining, flow cytometry, quantitative real-time polymerase chain reaction, and reciprocal bone marrow transplantation were used to evaluate the effect of TNC deficiency.
Results Echocardiographic analysis of pressure overloaded hearts revealed that all LV parameters (LV end-diastolic and -systolic dimensions, ejection fraction, and fractional shortening) deteriorated in TNC-deficient mice compared with their wild-type counterparts. Cardiomyocyte size and collagen accumulation were significantly greater in the absence of TNC. Mechanistically, TNC deficiency promoted rapid accumulation of the CCR2+/Ly6Chi monocyte/macrophage subset into the myocardium in response to pressure overload. Further, echocardiographic and immunohistochemical analyses of recipient hearts showed that expression of TNC in the bone marrow, but not the myocardium, protected the myocardium against excessive remodeling of the pressure-overloaded heart.
Conclusions TNC deficiency further impaired cardiac function in response to pressure overload and exacerbated fibrosis by enhancing inflammation. In addition, expression of TNC in the bone marrow, but not the myocardium, protected the myocardium against excessive remodeling in response to mild pressure overload.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received July 20, 2017.
- Revision received July 24, 2017.
- Accepted July 31, 2017.
- 2017 American College of Cardiology Foundation