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Myocardial Extracellular Matrix Remodeling in Hea

rt Failure

Myocardial Extracellular Matrix Remodeling in Hea

rt Failure

王小蕾 高新营 王洁 王淳阅 石琳

Myocardial remodeling

Myocardial remodeling

Myocardial Stress↑

Myocyteremodeling

Non-myocyteremodeling

ECMremodeling

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

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?

The MMPs and myocardial remodeling

How do the MMPs work in the remodeling process?

MMPactivation

Myocardialremodeling

Myocardialstress↑

Clinical evidence: a 30-fold increase in collagenase and gelatinase activity

a decrease in TIMP to negligible levels

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

The AV fistula experiment

MMP activity ＊ CVF

Ventricular

compliancecontractility size

Phase1 ↑↓in 3d

↑in 2w↑ ↓ ↑

Phase2 - - ↑ ↓ ↑

Phase3 ↑ ↑ ↓ ↑

＊ CVF: Collagen volume fraction

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↓

The AV fistula experiment

Method of testing MMP activity

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

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

>

Mature mast cell density

Role of cardiac mast cells in the activation of MMPs

remodeling normal

What is the

source for the

rapid increase

in mature mast density ?

Role of cardiac mast cells in the activation of MMPs

Mast cell degranulation

secreted substancesstimulate

maturation of mast cell

Myocardial stress ↑

The most possible source

Rapid maturation of resident cardiac mast cell precursors

Role of cardiac mast cells in the activation of MMPs

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.

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