Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction

Woodiwiss, Angela J.; Tsotetsi, Oupa J.; Sprott, S.; Lancaster, Eric; Mela, Theofanie; Chung, Eugene S.; Meyer, Theo E.; Norton, Gavin R.

doi:10.1161/01.cir.103.1.155

Cited by 174 publications

(172 citation statements)

References 32 publications

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“…One might expect a reduction in collagen accumulation to compromise the structural integrity of the myocardium (37). New collagen fibrils formed during the accelerated matrix turnover in experimental heart failure, however, are poorly crosslinked and structurally weak (38). Thus slowing the rapid cycle of collagen synthesis and degradation may be beneficial in attenuating both LV dilatation and diastolic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Murtuza

Suzuki

Bou‐Gharios

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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After myocardial infarction (MI), adverse remodeling with left ventricular (LV) dilatation is a major determinant of poor outcome. Skeletal myoblast (SkM) implantation improves cardiac function post-MI, although the mechanism is unclear. IL-1 influences post-MI hypertrophy and collagen turnover and is implicated in SkM death after grafting. We hypothesized that SkM expressing secretory IL-1 receptor antagonist (sIL-1ra) at MI border zones would specifically attenuate adverse remodeling and exhibit improved graft cell number. Stable murine male SkM lines (5 ؋ 10 5 cells), expressing or nonexpressing (cont) for sIL-1ra, were implanted into infarct border zones of female nude mice immediately after left coronary artery occlusion. LV ejection fraction (LVEF), end-diastolic diameter, and transmitral peak early͞late (E͞A) flow velocity ratio were determined by echocardiography. Cardiac myocyte hypertrophy and fibrosis were assessed by morphometry, picrosirius red staining, and hydroxyproline assay. At 3 weeks, cont-SkM-engrafted hearts showed reduced hypertrophy, improved LVEF (55.7 ؎ 1.2% vs. MI-only: 40.3 ؎ 2.9%), and preserved E͞A ratios. sIL-1ra-SkM implantation enhanced these effects (LVEF, 67.0 ؎ 2.3%) and significantly attenuated LV dilatation (LV end-diastolic diameter, 4.0 ؎ 1.1 mm vs. cont-SkM, 4.5 ؎ 1.2 mm vs. MI-only, 4.8 ؎ 1.8 mm); this was associated with greater graft numbers, as shown by PCR for male-specific smcy gene. Enzyme zymography showed attenuated matrix metalloproteinase-2 and -9 up-regulation post-MI by either donor SkM type, although infarct-remote zone collagen was reduced only with sIL-1ra-SkM. These results suggest that SkM implantation improves cardiac function post-MI by modulation of adverse remodeling, and that this effect can be significantly enhanced by targeting IL-1 as a key upstream regulator of both adverse remodeling and graft cell death.

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Section: Discussionmentioning

confidence: 99%

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Murtuza

Suzuki

Bou‐Gharios

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…4,16,37,38 Benjamin et al 39 proposed that increased fibrosis after Iso treatment was predominantly related to myocyte necrosis. Increased cell necrosis confined to the subendocardial region induced by Iso treatment has been attributed to the increased susceptibility of subendocardial cells to ischemia.…”

Section: Ennis Et Al Nhe-1 Inhibition In Isoproterenol-induced Hypertmentioning

confidence: 99%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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Abstract-Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either ␣-or ␤-adrenergic stimulation. Because an association between the Na ϩ /H ϩ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na ϩ /H ϩ exchanger activity (3 mg · kg) was given to male Wistar rats for 30 days. Sex-and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenolϩBIIB723-treated group. Heart weight-to-body weight ratio at necropsy was 2.44Ϯ0.11 in controls and increased to 3.35Ϯ0.10 (PϽ0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82Ϯ0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na ϩ /H ϩ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45Ϯ0.11 vs 0.91Ϯ0.05 arbitrary units, PϽ0.05). This effect was significantly reduced by BIIB723 (1.17Ϯ0.02, PϽ0.05). In conclusion, our results show that Na ϩ /H ϩ exchanger inhibition prevented the development of isoproterenolinduced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy. Key Words: hypertrophy, cardiac Ⅲ signal transduction Ⅲ antiporters Ⅲ fibrosis Ⅲ adrenergic receptor agonists I ncreased sympathetic activity is often implicated in the development of cardiac hypertrophy (CH). A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, 5-7 the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1). This study provides evidence indicating a key role for NHE-1 activity as a mechanism underlying the development of CH and fibrosis induced by I...

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“…subcutaneously (Ϸ0.1 mL) for 5 months, 15 to a group of rats (11 SHR and 14 WKY) that received the same volume of the vehicle of ISO (0.1 mL of 0.9% saline) for 5 months, and to a group of rats (10 SHR and 12 WKY) that received no treatment until hemodynamic and interstitial changes were evaluated at 21 to 22 months of age. Rats at 21 to 22 months of age were included in the study in order to assess whether the effect of ISO on LV geometry, hemodynamics, and interstitial characteristics in SHR has similarities consistent with the LV changes noted in SHR during the period when decompensation and dilatation occurs.…”

Section: Experimental Groupsmentioning

confidence: 99%

“…15 Briefly, hearts were perfused retrogradely at a constant flow (12 mL/g wet heart weight) with 37°C physiological saline solution, and paced at 360 bpm with platinum electrodes attached to the left atrium and the apex of the heart. LV systolic and diastolic pressures were determined by use of a water-filled balloontipped catheter over a range of LV volumes.…”

Section: Isolated Perfused Heart Preparationsmentioning

confidence: 99%

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

et al. 2003

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Abstract-It is uncertain whether chronic ␤-adrenoreceptor (␤-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic ␤-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

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Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction

Abstract: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Cited by 174 publications

References 32 publications

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

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Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction

Abstract: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Cited by 174 publications

References 32 publications

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

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Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition