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Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na[sup.+] channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A[sup.[DELTA]/+]) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a[sup.[DELTA]/+] mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a[sup.[DELTA]/+] mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome., Author(s): Dieter Nuyens [1]; Milan Stengl [2]; Saran Dugarmaa [4]; Tom Rossenbacker [1]; Veerle Compernolle [1]; Yoram Rudy [5]; Jos F. Smits [3]; Willem Flameng [6]; Colleen E. Clancy [5]; [...]

Janssen, Ben J. A., Peter J. A. Leenders, and Jos F. M. Smits. Short-term and long-term blood pressure and heart rate variability in the mouse. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: R215-R225, 2000.--Knowledge on murine blood pressure and heart rate control mechanisms is limited. With the use of a tethering system, mean arterial pressure (MAP) and pulse interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice. The day-to-day variation of MAP and PI was stable from 5 days after surgery. Within each mouse (n = 9), MAP and PI varied by 21 [+ or -] 6 mmHg and 17 [+ or -] 4 ms around their respective 24-h averages (97 [+ or -] 3 mmHg and 89 [+ or -] 3 ms). Over 24-h periods, MAP and PI were bimodally distributed and clustered around two preferential states. Short-term variability of MAP and PI was compared between the resting (control) and active states using spectral analysis. In resting conditions, variability of MAP was mainly confined to frequencies [is less than] 1 Hz, whereas variability of PI was predominantly linked to the respiration cycle (3-6 Hz). In the active state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was high at 0.4 Hz with MAP leading the PI fluctuations by 0.3-0.4 s, suggesting that reflex coupling between MAP and PI occurred at the same frequency range as in rats. Short-term variability of MAP and PI was studied after intravenous injection of autonomic blockers. Compared with the resting control state, MAP fell and PI increased after ganglionic blockade with hexamethonium. Comparable responses of MAP were obtained with the [Alpha]-blocker prazosin, whereas the [Beta]-blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did not significantly alter steady-state levels of MAP and PI. Both hexamethonium and prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range. Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08- to 1-Hz range. These data indicate that, in mice, blood pressure and its variability are predominantly under sympathetic control, whereas both vagal and sympathetic nerves control PI variability. Blockade of endogenous nitric oxide formation by [N.sup.G]-nitro-L-arginine methyl ester increased MAP variability specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in buffering blood pressure fluctuations. autonomic control; baroreflex; circadian rhythm; set point; spectral analysis

Aims: The Wnt/frizzled (Fzd) signal transduction cascade has been implicated in the proliferation, differentiation, and migration of many cell types, but the role of this pathway in cardiac fibroblast differentiation is not known. Our lab previously showed an up-regulation of Fzd-1 and -2 expression in myofibroblasts after myocardial infarction (MI), indicating a potential role for the Fzd receptor in fibroblast–myofibroblast differentiation. The present study was performed to further define the role of specific Wnt and Fzd proteins in the proliferation, migration, and differentiation of cardiac fibroblasts. [ABSTRACT FROM PUBLISHER]

Wnt/β-catenin signaling is an important regulator of cell polarity, proliferation, and stem cell maintenance during development and adulthood. Wnt proteins induce the nuclear accumulation of β-catenin, which regulates the expression of Wnt-responsive genes through association with TCF/LEF transcription factors. Aberrant Wnt/β-catenin signaling has been implicated in a plethora of pathologies and, most notably, underlies initiation and expansion of several cancers. Here, we apply enzyme fragment complementation to measure the nuclear accumulation of β-catenin. β-Catenin was tagged with a peptide fragment of β-galactosidase and transfected into cells expressing a corresponding deletion mutant of the enzyme exclusively in the nucleus. Stimulation of the cells with recombinant Wnt-3a restored β-galactosidase activity in a dose-dependent manner with nanomolar potency. Using the assay, we confirmed that Wnt-5a represses β-catenin-driven reporter gene activity downstream of nuclear entry of β-catenin. In addition, we tested a library of >2000 synthetic chemical compounds for their ability to induce β-catenin nuclear accumulation. The immunosuppressive protein kinase C inhibitor sotrastaurin (AEB-071) was identified as an activator of Wnt/β-catenin signaling at micromolar concentrations. It was confirmed that the compound stabilizes endogenous β-catenin protein and can induce TCF/LEF-dependent gene transcription. Subsequent biochemical profiling of >200 kinases revealed both isoforms of glycogen synthase kinase 3, as previously unappreciated targets of sotrastaurin. We show that the β-catenin nuclear accumulation assay contributes to our knowledge of molecular interactions within the Wnt/β-catenin pathway and can be used to find new therapeutics targeting Wnt/β-catenin signaling. [ABSTRACT FROM AUTHOR]

Aims: Our objective was to study the effect of the genetic background on the wound healing process after myocardial infarction (MI) in mice. [ABSTRACT FROM PUBLISHER]

BACKGROUND Hypertensive target organ damage shows characteristics of accelerated cell turnover and aging. This might have developed during the evolution of hypertension. In the kidney, high cell turnover is mainly restricted to tubular cells. It was the aim of this study to investigate whether a transient intervention in spontaneously hypertensive rats (SHRs) leads to reduced tubular cell turnover and attenuates the renal aging process and tubulo-interstitial damage in the long-term. METHODS SHRs (i) were prehypertensively (weeks 4-8) treated with losartan (ii) or hydralazine (iii) (20 and 4 mg/kg/day, respectively) and compared to Wistar-Kyoto (WKY) rats (iv). Groups were investigated at weeks 8 and 72 (except iii). At both time points tubular cell proliferation (proliferative cell nuclear antigen) and systolic blood pressure (SBP) were evaluated. At week 72, aging parameters such as telomere length were assessed. Renal damage was semiquantitatively assessed (scale: 0-4) by measuring the parenchyma (atrophy) and vasculature (media thickness). RESULTS Treatments equipotently reduced SBP in young SHRs (P < 0.01) but only losartan reduced renal proliferation (proliferative cell nuclear antigen: (i) 2.8 ± 0.8, (ii) 1.3 ± 0.3, (iii) 3.0 ± 0.6, (iv) 0.1 ± 0.1 cells/mm2). In SHRs treated with losartan(SHR-Los) tubular proliferation remained reduced and renal telomere length was significantly greater than in untreated SHRs (fold: (i) 1.0 ± 0.1, (ii) 2.8 ± 0.3, P < 0.01). Untreated SHRs (median 2.0, range 1-3; P < 0.007), but not SHR-Los (median 1.0, range 0-2; P = 0.06) demonstrated more tubular atrophy than WKY rats (median 0.5, range 0-1). CONCLUSIONS Transient losartan treatment reduces cell-turnover not only acutely but also for a prolonged period after drug withdrawal. This results in the long-term in reduced aging and attenuated tubulo-interstitial damage, suggesting there exists a modulating effect of angiotensin II (ANGII)-antagonism on long-term cell turnover. [ABSTRACT FROM AUTHOR]

The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein. Disheveled subsequently can inhibit glycogen synthase kinase-3beta, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3beta leads to an increased amount of beta-catenin, which can act as a transcription factor for several hypertrophy-associated target genes. In this study we subjected mice lacking the Dvl-1 gene and their wild-type littermates to thoracic aortic constriction for 7, 14, and 35 days. In mice lacking the Dvl-1 gene, 7 days of pressure overload-induced increases in left ventricular posterior wall thickness and expression of atrial natriuretic factor and brain natriuretic protein were attenuated compared with their wild-type littermates. Beta-catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3beta activity was observed. Moreover, the increase in the amount of Ser(473)-phosphorylated Akt, a stimulator of cardiac hypertrophy, was lower in the group lacking the Dvl-1 gene. In conclusion, we have demonstrated that interruption of Wnt signaling in the mice lacking the Dvl-1 gene attenuates the onset of pressure overload-induced cardiac hypertrophy through mechanisms involving glycogen synthase kinase-3beta and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy. [ABSTRACT FROM AUTHOR]

Studies the expression and localization of renin and andigotensinogen in rat heart after myocardial infarction. Cardiac hypertrophy among different compartments; Levels of renin/angiotensinogen mRNA levels; Localization of renin/angiotensinogen mRNA.