ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Human myocardium has long been considered to have essentially no intrinsic regenerative capacity. Recent studies in rodent models, however, have suggested the presence of an extracardiac stem cell population, perhaps in bone marrow, that is capable of some reconstitution of cardiomyocytes after injury. To determine whether similar mechanisms exist in the human heart, we evaluated human female allograft hearts transplanted into male patients. The presence of Y chromosomes in cardiomyocytes would indicate these cells arose from the recipient, rather than the donor heart. We identified 5 male patients who had retained a female heart at least 9 months before death and necropsy. Remarkably, in each case, the transplanted heart contained a minute but readily detectable fraction of Y chromosome-positive cardiomyocytes. The mean percentage of cardiomyocytes arising from the host was estimated to be 0.04% with a median of 0.016%. Most Y-positive cardiomyocytes were associated with regions of acute rejection, suggesting such chimerism involves an injury event. Furthermore, the sole patient whose immediate cause of death was allograft rejection showed a much higher percentage of host-derived cardiomyocytes, up to 29% in local, 1-mm2“hot spots.” Thus, adult humans have extracardiac progenitor cells capable of migrating to and repopulating damaged myocardium, but this process occurs at very low levels.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

To test the hypothesis that early interventional treatment with insulin-like growth factor-1 (IGF-1) alleviates subsequent development of dilated cardiomyopathy, cardiac-specific IGF-1 expression was introduced by selective cross-breeding into a transgenic mouse model of heart failure that displays phenotypic characteristics of severe dilation. Hemodynamic, structural, and cellular parameters of the heart were compared between nontransgenic, tropomodulin-overexpressing cardiomyopathic, and the hybrid tropomodulin/IGF-1-overexpressing mice. Beneficial effects of IGF-1 were apparent by multiple indices of cardiac structure and function, including normalization of heart mass, anatomy, hemodynamics, and apoptosis. IGF-1 expression also acted as a proliferative stimulus as evidenced by calculated increases in myocyte number as well as expression of Ki67, a nuclear marker of cellular replication. Cellular analyses revealed that IGF-1 inhibited characteristic cardiomyocyte elongation in dilated hearts and restored calcium dynamics comparable to that observed in normal cells. Collectively, these results provide novel information regarding the ability of IGF-1 to inhibit progression of cardiomyopathic disease in a defined model system and suggest that heart failure may benefit from early interventional IGF-1 treatment.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The cardiac myofilament protein troponin I (cTnI) is phosphorylated by protein kinase C (PKC), a family of serine/threonine kinases activated within heart muscle by a variety of agonists. cTnI is also a substrate for cAMP-dependent protein kinase (PKA) activated during &bgr;-adrenergic signaling. To investigate the role of cTnI phosphorylation in contractile regulation by these pathways, we generated transgenic mice harboring a mutated cTnI protein lacking phosphorylation sites for PKC (serine43/45and threonine144mutated to alanine) and for PKA (serine23/24mutated to alanine). Transgenic mice were interbred with cTnI-knockout mice to ensure the absence of endogenous phosphorylatable cTnI. Here, we report that regulation of myocyte twitch kinetics by &bgr;-stimulation and by endothelin-1 was altered in myocytes containing mutant cTnI. In wild-type myocytes, the &bgr;-agonist isoproterenol decreased twitch duration and relaxation time constant (&tgr;) by 37% to 44%. These lusitropic effects of isoproterenol were reduced by about half in nonphosphorylatable cTnI mutant myocytes and were absent in cTnI mutants also lacking phospholamban (generated by crossing cTnI mutants with phospholamban-knockout mice). These observations are consistent with important roles for both cTnI and phospholamban phosphorylation in accelerating relaxation after &bgr;-adrenergic stimulation. In contrast, endothelin-1 increased twitch duration by 32% and increased &tgr; by 58%. These endothelin-1 effects were substantially blunted in nonphosphorylatable cTnI myocytes, indicating that PKC phosphorylation of cTnI slows cardiac relaxation and increases twitch duration. We propose that &bgr;-agonists and endothelin-1 regulate cardiac twitch dynamics in opposite directions in part through phosphorylation of the myofilament protein cTnI on distinct sites.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4±4.6, WT 85.8±4.2, TG 72.4±2.4 mm Hg [mean±SE],P<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%&Dgr;RPP 10−7mol/L ACh: KO −48.1±3.9%, WT −57.5±5.6%, TG −22.8±4.8%,P<0.01), whereasNG-nitro-l-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%&Dgr;RPP 10−4mol/L: KO 33.1±3.3%, WT 55.5±7.2%, TG 152.6±21.2%,P<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%&Dgr;RPP 10−6mol/L CGRP(8-37): KO 12.8±2.6%, WT 19.4±3.6%, TG 41.8±8.7%,P<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104±5>WT 98±15>TG 38±7 mg/dL,P<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Strong electrical shocks can induce arrhythmias, which might explain why shocks fail to defibrillate. In this work, the localization of arrhythmia source and the relationship with local changes of transmembrane potential (Vm) were determined in geometrically defined cell cultures using optical mapping technique. Uniform-field shocks with strength (E) of 10 to 50 V/cm were applied across cell strands with width of 0.2 and 0.8 mm. The threshold for arrhythmia induction was dependent on the strand width: in the 0.8- and 0.2-mm strands, arrhythmias were induced at E≥20.6±1.8 V/cm (n=8) and E≥30.3±1.8 V/cm (n=8), respectively. At the same shock strength, the arrhythmia rate and duration were larger in the wider strands. During shocks that induced arrhythmias, the Vmwaveforms on the anodal side revealed a positive Vmshift that followed the initial large hyperpolarization and postshock elevation of the diastolic Vm. These Vmchanges were absent during failed shocks. To determine the localization of the arrhythmia source, arrhythmias were induced in narrow cell strands containing regions of local expansion. Optical mapping of the first extrabeat with a coupling interval of 315±60 ms revealed that in the majority of cases (9 out of 13) the source of arrhythmias was localized in the areas of shock-induced hyperpolarization. Thus, (1) induction of postshock arrhythmias, their rate, and their duration strongly depend on the tissue structure; (2) arrhythmia induction coincides with the appearance of a positive Vmshift in the areas of hyperpolarization; and (3) the source of postshock arrhythmias is located in the areas of shock-induced hyperpolarization.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID