AEROBIC AND ANAEROBIC SCALING IN FISH

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75506/1/j.1469-185X.1991.tb01134.x.pd

TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy

Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca(2+)-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP(3)) is responsible for Ca(2+) increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP(3) is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca(2+) oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca(2+) channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca(2+) signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy

Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the remodeling process remain poorly defined. Patients with heart failure after MI have reduced LV expression levels of muscle LIM protein (MLP), a component of the sarcomeric Z-disk that is involved in the integration of stress signals in cardiomyocytes. By using heterozygous MLP mutant (MLP(+/—)) mice, we explored the role of MLP in post-MI remodeling. LV dimensions and function were similar in sham-operated WT and MLP(+/—) mice. After MI, however, MLP(+/—) mice displayed more pronounced LV dilatation and systolic dysfunction and decreased survival compared with WT mice, indicating that reduced MLP levels predispose to adverse LV remodeling. LV dilatation in MLP(+/—) mice was associated with reduced thickening but enhanced elongation of cardiomyocytes. Activation of the stress-responsive, prohypertrophic calcineurin–nuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP(+/—) mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP(+/—)/NFAT-luciferase reporter gene transgenic mice. Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP(+/—) mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk. In vitro assays in cardiomyocytes with down-regulated MLP confirmed that MLP is required for stress-induced calcineurin–NFAT activation. Our study reveals a link between the stress sensor MLP and the calcineurin–NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP–calcineurin signaling predisposes to adverse remodeling after MI

Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway

Aims: Cyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date, the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to pathological cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL. Methods and results: Mice lacking the Cn-Aβ subunit (CnAβ -/-) and wild-type (WT) controls were subjected to transverse aorta constriction (TAC) with or without SIL (200 mg/kg/day, p.o.) for 3 weeks. TAC-induced elevation of Cn expression and activity in WT was absent in CnAβ-/- hearts, and the latter accordingly developed less cardiac hypertrophy (50 vs. 100% increase in heart weight/tibia length, P<0.03) and chamber dilation. SIL remained effective in CnAβ-/- mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC-stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3β in both groups (the first rising more in CnAβ-/- hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnAβ-/- hearts was also suppressed by SIL. Conclusion: PDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.9 page(s

Impaired cardiac hypertrophic response in Calcineurin Aβ-deficient mice

Calcineurin is a calcium–calmodulin-regulated, serine–threonine phosphatase that functions as a key inducer of stress responsive gene expression in multiple cell types through a direct activation of nuclear factor of activated T cells and myocyte enhancer factor 2 transcription factors. In cardiomyocytes, calcineurin signaling has been implicated in the regulation of the hypertrophic response caused by pressure overload or neuroendocrine stimulation. Three separate genes encode the catalytic subunit of calcineurin in mammalian cells, CnAα, CnAβ, and CnAγ. To evaluate the necessary function of calcineurin as a hypertrophic regulatory factor, the CnAβ gene was disrupted in the mouse. CnAβ-deficient mice were viable, fertile, and overtly normal well into adulthood, but displayed a 80% decrease in calcineurin enzymatic activity in the heart that was associated with a 12% reduction in basal heart size. CnAβ-deficient mice were dramatically impaired in their ability to mount a productive hypertrophic response induced by pressure overload, angiotensin II infusion, or isoproterenol infusion. Analysis of marker genes associated with the hypertrophic response revealed a partial defect in the molecular program of hypertrophy. Collectively, these data solidify the hypothesis that calcineurin functions as a central regulator of the cardiac hypertrophic growth response in vivo