Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts

Kerckhoven, Roeland Van; Kalkman, Ed A.J.; Saxena, Pramod R.; Schoemaker, Regien G.

doi:10.1016/s0008-6363(99)00427-7

Cited by 30 publications

(27 citation statements)

References 25 publications

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“…It is therefore conceivable that KH064 exerts its antifibrotic effects through regulation of PGE 2 release, which in turn affects MMP that directly regulate collagen deposition. The reduction of fibrosis by cyclooxygenase inhibitors such as aspirin (43) lends support to this idea. However, substantial further detailed studies are required to determine any links between individual sPLA 2 enzymes, release of specific arachidonate metabolites, activation of specific MMPs, collagen deposition, and cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 91%

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Levick¹,

Loch²,

Rolfe³

et al. 2006

The Journal of Immunology

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The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A2 (sPLA2-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA2-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 ± 0.9%, n = 5; SHR+KH064 14.0 ± 1.2%, n = 5) and interstitial (SHR 7.9 ± 0.3%, n = 6; SHR+KH064 5.4 ± 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 ± 0.08, n = 12; SHR+KH064 3.09 ± 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA2-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.

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Section: Discussionmentioning

confidence: 91%

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Levick¹,

Loch²,

Rolfe³

et al. 2006

The Journal of Immunology

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“…Support for this supposition can be found in the earlier observations of Gervais et al (10), who showed that in young infarcted rats in which hypertrophy had been prevented but myocardial fibrosis had been allowed to develop naturally, perfusion within the surviving LV myocardium was not fully restored. On the basis of this accumulating evidence, we hypothesized that in infarcted middle-aged rats the extent of perivascular fibrosis may affect myocardial perfusion.Although there have been reports indicating that fibrosis of coronary arteries does not contribute to the regulation of myocardial perfusion in infarcted rats (13,17,24,29), the effects of fibrosis in the coronary arterioles has never been evaluated. Thus we designed our current study to investigate whether the extent of periarteriolar collagen is a factor in maximal myocardial perfusion in infarcted middle-aged rats in which adaptive arteriolar growth occurs in response to chronic HRR.…”

mentioning

confidence: 99%

“…Although there have been reports indicating that fibrosis of coronary arteries does not contribute to the regulation of myocardial perfusion in infarcted rats (13,17,24,29), the effects of fibrosis in the coronary arterioles has never been evaluated. Thus we designed our current study to investigate whether the extent of periarteriolar collagen is a factor in maximal myocardial perfusion in infarcted middle-aged rats in which adaptive arteriolar growth occurs in response to chronic HRR.…”

mentioning

confidence: 99%

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Dedkov¹,

Zheng²,

Christensen³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Dedkov EI, Zheng W, Christensen LP, Weiss RM, MahlbergGaudin F, Tomanek RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol 293: H590-H598, 2007. First published March 23, 2007; doi:10.1152/ajpheart.00047.2007.-We tested the hypothesis that chronically reducing the heart rate in infarcted middle-aged rats using ivabradine (IVA) would induce arteriolar growth and attenuate perivascular collagen and, thereby, improve maximal perfusion and coronary reserve in the surviving myocardium. Myocardial infarction (MI) was induced in 12-mo-old male Sprague-Dawley rats, which were then treated with either IVA (10.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; MI ϩ IVA) or placebo (MI) via intraperitoneal osmotic pumps for 4 wk. Four weeks of IVA treatment limited the increase in left ventricular end-diastolic pressure and the decrease in ejection fraction but did not affect the size of the infarct, the magnitude of myocyte hypertrophy, or the degree of arteriolar and capillary growth. However, treatment reduced interstitial and periarteriolar collagen in the surviving myocardium of MI ϩ IVA rats. The reduced periarteriolar collagen content was associated with improvement in maximal myocardial perfusion and coronary reserve. Although the rates of proliferation of periarteriolar fibroblasts were similar in the MI and MI ϩ IVA groups, the expression levels of the AT 1 receptor and transforming growth factor (TGF)-␤1 in the myocardium, as well as the plasma level of the ANG II peptide, were lower in treated rats 14 days after MI. Therefore, our data reveal that improved maximal myocardial perfusion and coronary reserve in MI ϩ IVA rats are most likely the result of reduced periarteriolar collagen rather than enhanced arteriolar growth. myocardial infarction; coronary circulation; coronary vessels; reninangiotensin system A MYOCARDIAL INFARCTION (MI) initiates progressive structural remodeling within the surviving left ventricular (LV) myocardium. Features of such remodeling include cardiac myocyte hypertrophy, fibroblast proliferation, and interstitial/perivascular fibrosis (4, 26). These alterations compromise maximal coronary blood perfusion and coronary reserve in the remaining LV myocardium (5,6,15,16,18,20).Since adequate tissue perfusion is key for survival and effective function of hypertrophied myocytes in the remaining overloaded LV myocardium, the recovery of normal tissue perfusion in this region has become a major focus of several studies (14, 15), including those from our laboratory (5, 20). Because the major cause of limited myocardial perfusion and coronary reserve in post-MI hearts was long thought to be a failure to match the adaptive growth of the intramyocardial vasculature to the degree of myocyte hypertrophy, earlier studies, which were conducted on young and young-adult rats, were designed either to reduce myocyte hypertrophy (14,24) or to promote the growth of the coronary vasculature (20).MI i...

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“…Alterations in the ECM, such as increased collagen accumulation and changes in matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs), have been observed in the remote myocardium after MI. [3][4][5] The ECM sustains myocardial structure and functional properties and collagen turnover is controlled by specific MMPs and TIMPs under normal hemodynamic conditions. Changes in ECM composition have been shown to coincide with myocardial ischemia and dilated cardiomyopathy; 6 however, the underlying cellular and molecular changes are not yet completely understood.…”

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confidence: 99%

Selective Down-Regulation of Extracellular Matrix Gene Expression by Bone Marrow Derived Stem Cell Transplantation Into Infarcted Myocardium

et al. 2005

Circ J

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eft ventricular (LV) remodeling involves expansion of the infarcted area, ventricular dilatation, and thinning of the ventricular wall after a myocardial infarction (MI). 1,2 The dynamic synthesis and breakdown of extracellular matrix (ECM) proteins may play an important role in myocardial remodeling. Remodeling after MI is associated with LV dilation, decreased cardiac function, and increased mortality. In the early stage immediately after MI, the infarcted region of the LV undergoes myocyte necrosis, apoptosis, and ECM reorganization. Alterations in the ECM, such as increased collagen accumulation and changes in matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs), have been observed in the remote myocardium after MI. [3][4][5] The ECM sustains myocardial structure and functional properties and collagen turnover is controlled by specific MMPs and TIMPs under normal hemodynamic conditions. Changes in ECM composition have been shown to coincide with myocardial ischemia and dilated cardiomyopathy; 6 however, the underlying cellular and molecular changes are not yet completely understood.MI leads to tissue loss and impaired cardiac perfor- mance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. 7 Although surgical and interventional revascularization of the ischemic myocardium can treat angina, reduce the risk of further MI, and improve the function of viable myocardium, the viability of necrotic myocardium cannot be restored. Therefore, the search for new and effective therapeutic methods is warranted. In recent years, cell transplantation has emerged as a novel approach for generation of viable heart muscle cells. Experimental data show that transplantation of bone marrow stem cells or neonatal myocytes could regenerate functional myocardium and improve ventricular function in animals with MI. [8][9][10][11] In the meantime, myogenic cells may provide elasticity to stabilize the infarct region and prevent infarct thinning, chamber dilatation, and congestive heart failure. 12 In the present study, we set out to isolate and expand a highly purified population of adult rat bone marrow derived stem cells (MSCs), and to test the hypothesis that MSCs could prevent remodeling, improve heart function and reduce ECM gene expression after their transplantation into infarcted myocardium. Methods AnimalsAdult male Wistar rats weighing 250-300 g were purchased from the Laboratory Animal Center of the Chinese Academy of Medical Sciences. Rats were housed at a constant temperature (20°C) and humidity (45%) on a 12-h light/dark cycle. They were fed ad libitum on standard laboratory rat chow and had free access to tap water. All rats were given 5-7 days to adjust to their new environment. Background Myocardial fibrosis is a major component of ventricular remodeling after myocardial infarction (MI). The aim of the present study was to determine the outcome of transplantation into ischemic myocardium of bone marrow deri...

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Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts

Abstract: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.

Cited by 30 publications

References 25 publications

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Selective Down-Regulation of Extracellular Matrix Gene Expression by Bone Marrow Derived Stem Cell Transplantation Into Infarcted Myocardium

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