1. LOGO Myocardial Extracellular Matrix Remodeling in Heart Failure 王小蕾 高新营 王洁 王淳阅 石琳

2. Myocardial remodeling Myocardial remodeling Myocardial Stress ↑ Myocyte remodeling Non-myocyte remodeling ECM remodeling

3. ECM remodeling in the heart Collagen I （ 80% ） III （ 10-15% ） V （ <5% ）  Components Fibronectin, Laminin, Elasin  Function: interconnecting the cardiomyocytes maintaining ventricular shape, size, stiffness Normal Remodeling Caused by the MMPs The imbalance of degradation and synthesis of collagen

4. The MMPs and myocardial remodeling  The Matrix MetalloProteinases family(>20 kinds) Collagenases: MMP-1, MMP-8, MMP-13 Gelatinases: MMP-2, MMP-9  Abundant collagenases are present in the heart, but only 1%-2% of them are active in physiologicstatus  TIMP (Tissue Inhibitors of MetalloProteinases) What are the MMPs?

5. The MMPs and myocardial remodeling How do the MMPs work in the remodeling process? MMP activation Myocardial remodeling Myocardial stress ↑ Clinical evidence: a 30-fold increase in collagenase and gelatinase activity a decrease in TIMP to negligible levels

6. MMP activity in volume overload Model: Chronic biventricular volume overload using aorta-caval fistula rat model Result : the post-fistula patho-physiologic course 1.The initial phase: 0-2 weeks, no deaths 2.The compensated hypertrophic phase: variable duration 3.The decompensated phase:100% dead by 30 weeks Experiment

7. The AV fistula experiment MMP activity ＊ CVF Ventricular compliance contractilitysize Phase1 ↑ ↓in 3d ↑in 2w ↑↓↑ Phase2 - - ↑↓↑ Phase3 ↑↑↓↑ ＊ CVF: Collagen volume fraction

8. The AV fistula experiment Phase1: MMP activity ↑ within 12h; collagen volume fraction(CVF) ↓ by 3d, quickly ↑, above normal by 14d; ventricular dilatation and hypertrophy by 7d; ventricular compliance ↑,contractility ↓ Changes in the first phase More compliant collagen III ↑ Collagen cross-linking ↓

9. The AV fistula experiment Method of testing MMP activity

10. The AV fistula experiment MMP activation in the early stages of injury or elevated wall stress and the consequent degradation of collagen are responsible for the initiation of a progressive remodeling process that leads to heart failure. Conclusion

11. Role of cardiac mast cells in the activation of MMPs  In the AV fistula modle: Mast cell density: 12h~5d MMP activity: 12h~14d the compensated hypertrophy phase  Mast cell stabilizing drug effectively prevents the LV dilatation, increased compliance and decreased contractility

12. > Mature mast cell density Role of cardiac mast cells in the activation of MMPs remodelingnormal What is the source for the rapid increase in mature mast density ?

13. Role of cardiac mast cells in the activation of MMPs Mast cell degranulation secreted substances stimulate maturation of mast cell Myocardial stress ↑ The most possible source Rapid maturation of resident cardiac mast cell precursors

14. Role of cardiac mast cells in the activation of MMPs

15. Reference 1.Joseph S. Janicki, Gregory L. Brower, Jason D. Gardner, Mary F. Forman, James A. Stewart, Jr., David B. Murray and Amanda L. Chancey, Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload, Cardiovascular Research, Volume 69, Issue 3, 15 February 2006, Pages 657-665 2.Anne M. Deschamps and Francis G. Spinale, Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation, Cardiovascular Research, Volume 69, Issue 3, 15 February 2006, Pages 666-676 3.Stefanie Gilles, Stefan Zahler, Ulrich Welsch,Christian P. Sommerhoff, Bernhard F. Becker, Release of TNF-a during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers, Cardiovascular Research,2003;60:608– 616 4.Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001;11:372– 7 5.Dempsey PW, Doyle SE, He JQ, Cheng G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 2003;14:193–209 6.Stefanie Gilles, Stefan Zahler, Ulrich Welschb,Christian P. Sommerhoff, Bernhard F. Beckera, Release of TNF-a during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers, Cardiovascular Research, 60 ;2003:608– 616 7.Brower GL, Henegar JR, Janicki JS. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload. Am J Physiol Heart Circ Physiol 1996;271:H2071– 8 8.Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale FG, et al. Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol 2003;284:H122 – 32.

16. LOGO