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Biomedical subjects

G E Taffet

Publications and source records attributed to G E Taffet.

At least 19 recordsLinked to original sources
PubMed2001

Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival.

Cardiac muscle regeneration after injury is limited by "irreversible" cell cycle exit. Telomere shortening is one postulated basis for replicative senescence, via down-regulation of telomerase reverse transcriptase (TERT); telomere dysfunction also is associated with greater sensitivity to apoptosis. Forced expression of TERT in cardiac muscle in mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte density and DNA synthesis. By 12 wk, cell cycling subsided; instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function. Likewise, viral delivery of TERT was sufficient for hypertrophy in cultured cardiac myocytes. The TERT virus and transgene also conferred protection from apoptosis, in vitro and in vivo. Hyperplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in postmitotic cells, and promote cardiac myocyte survival.

Animals↗
PubMed2000

Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction.

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

Acute Disease↗
PubMed2000

TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice.

The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

Activating Transcription Factor 6↗
PubMed2000

A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies.

Reperfusion of the ischemic myocardium is associated with a cytokine cascade that reflects a cellular response to injury. We studied this cascade in the mouse and found that acute surgical trauma in sham-operated animals obscured early changes in cytokine induction that occur during myocardial ischemia-reperfusion (MI/R). Therefore, we utilized a new implantable device that allows occlusion and reperfusion of the left anterior descending coronary artery in a closed-chest mouse at any time after instrumentation. Induction of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha mRNA in the whole heart was examined by RNase protection assay and quantitated by Phosphor- Imager. At 3 h after instrumentation, levels of IL-6 mRNA in sham-operated animals increased above those of control naive hearts, whereas this increase did not occur until after 1 day for TNF-alpha mRNA. The surgical trauma led to exaggeration of I/R cytokine induction with greater variance in response. At 3 days and 1 wk after instrumentation, levels of both IL-6 and TNF-alpha mRNA in sham-operated animals were comparable to those of naive hearts and induction responses in I/R were much less variant. We also found that 1 h of ischemia and 2 h of reperfusion at all time points of recovery (i.e., 3 h and 1, 3, and 7 days after instrumentation) led to a significant increase in IL-6 and TNF-alpha mRNA levels. In addition, 3 h of permanent occlusion, which did not induce any mRNA increase after 1 wk postinstrumentation, caused marked upregulation of IL-6 mRNA in an acutely prepared animal. This study of early cytokine responses evoked by MI/R highlights the need for dissipation of acute surgical trauma by using a chronic, closed-chest mouse preparation.

Animals↗
PubMed2000

Hemodynamic changes in apolipoprotein E-knockout mice.

Apolipoprotein E-knockout (ApoE-KO) mice develop advanced atherosclerotic lesions by 1 yr of age and have been well characterized pathologically and morphologically, but little is known regarding their cardiovascular physiology and hemodynamics. We used noninvasive Doppler ultrasound to measure aortic and mitral blood velocity and aortic pulse-wave velocity in 13-mo-old ApoE-KO and wild-type (WT) mice anesthetized with isoflurane. In other mice from the same colony, we measured systolic blood pressure, body weight, heart weight, cholesterol, and hematocrit. Heart rate and blood pressure were comparable (P = not significant) between ApoE-KO and WT mice, but significant decreases (P < 0.001) were found in body weight (-22%) and hematocrit (-11%), and significant increases were found in heart weight (+23%), aortic velocity (+60%), mitral velocity (+81%) (all P < 0.001), and pulse-wave velocity (+13%, P < 0.05). We also found inflections in the aortic arch velocity signal consistent with enhanced peripheral wave reflection. Thus ApoE-KO mice have phenotypic alterations in indexes of peripheral vascular resistance and compliance and significantly elevated cardiac outflow velocities and heart weight-to-body weight ratios.

Animals↗
PubMed1999

The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function.

Desmin is the muscle-specific member of the intermediate filament family of cytoskeletal proteins, expressed both in striated and smooth muscle tissues. In mature striated muscle fibers, the desmin filament lattice surrounds the Z-discs, interconnects them to each other and links the entire contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles and the nucleus. There have been increasing reports of human cardiomyopathies associated with abnormal accumulation and aggregation of desmin filaments. Recently identified desmin mutations in humans suffering from skeletal muscle myopathy and cardiomyopathy suggest that these diseases might arise as a consequence of impaired function of desmin filaments. Previous generation of desmin null mice in our laboratory demonstrated that the absence of desmin results in myocyte ultrastructural defects and myocyte cell death leading to fibrosis and calcification of the myocardium. However, the effects that these defects have on cardiac function were not addressed. To further our understanding of desmin function in vivo, and in order to address the direct involvement of desmin in cardiomyopathy, we investigated the effect of the absence of desmin on myocardial mass, myocyte size and shape, changes in gene expression and cardiac systolic and diastolic function in mice. Morphometric characterization of isolated cardiomyocytes demonstrated a 24% increase in cell volume in the desmin null mice, solely due to an increase in transverse section area, suggesting for the first time that mice lacking the intermediate filament protein desmin develop concentric cardiomyocyte hypertrophy. This type of hypertrophy was accompanied by induction of embryonic gene expression and later by ventricular dilatation, and compromised systolic function. These results demonstrate that desmin is essential for normal cardiac function, and they suggest that the absence of an intact desmin filament system, rather than accumulation of the protein, may be responsible for the pathology seen in some of the desmin associated cardiomyopathies.

Animals↗
PubMed1999

Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice.

In the present study we determined the long-term effects of persistent, local insulin-like growth factor I (IGF-I) expression on cardiac function in the SIS2 transgenic mouse. Cardiac mass/tibial length was increased in SIS2 mice by 10 wk of age; this cardiac hypertrophy became more pronounced later in life. Peak aortic outflow velocity, a correlate of cardiac output, was increased at 10 wk in SIS2 mice but was decreased at 52 wk. 72 wk SIS2 mouse hearts exhibited wide variability in the extent of cardiac hypertrophy and enlargement of individual cardiac myofibers. Sirius red staining revealed increased fibrosis in 72 wk SIS2 hearts. Persistent local IGF-I expression is sufficient to initially induce an analog of physiological cardiac hypertrophy in which peak aortic outflow velocity is increased relative to controls in the absence of any observed detrimental histological changes. However, this hypertrophy progresses to a pathological condition characterized by decreased systolic performance and increased fibrosis. Our results confirm the short-term systolic performance benefit of increased IGF-I, but our demonstration that IGF-I ultimately diminishes systolic performance raises doubt about the therapeutic value of chronic IGF-I administration. Considering these findings, limiting temporal exposure to IGF-I seems the most likely means of delivering IGF-I's potential benefits while avoiding its deleterious side effects.

Animals↗
PubMed1999

Myocardial infarction and remodeling in mice: effect of reperfusion.

Anatomic and functional changes after either a permanent left anterior descending coronary artery occlusion (PO) or 2 h of occlusion followed by reperfusion (OR) in C57BL/6 mice were examined and compared with those in sham-operated mice. Both interventions generated infarcts comprising 30% of the left ventricle (LV) measured at 24 h and equivalent suppression of LV ejection velocity and filling velocity measured by Doppler ultrasound at 1 wk. Serial follow-up revealed that the ventricular ejection velocity and filling velocity returned to the levels of the sham-operated controls in the OR group at 2 wk and remained there; in contrast, PO animals continued to display suppression of both systolic and diastolic function. In contrast, ejection fractions of PO and OR animals were depressed equivalently (50% from sham-operated controls). Anatomic reconstruction of serial cross sections revealed that the percentage of the LV endocardial area overlying the ventricular scar (expansion ratio) was significantly larger in the PO group vs. the OR group (18 +/- 1.7% vs. 12 +/- 0.9%, P < 0.05). The septum that was never involved in the infarction had a significantly (P < 0.002) increased mass in PO animals (22.5 +/- 1.08 mg) vs. OR (17.8 +/- 1.10 mg) or sham control (14.8 +/- 0.99 mg) animals. Regression analysis demonstrated that the extent of septal hypertrophy correlated with LV expansion ratio. Thus late reperfusion appears to reduce the degree of infarct expansion even under circumstances in which it no longer can alter infarct size. We suggest that reperfusion promoted more effective ventricular repair, less infarct expansion, and significant recovery or preservation of ventricular function.

Animals↗
PubMed1998

Membrane asymmetry in isolated canine cardiac sarcoplasmic reticulum: comparison with skeletal muscle sarcoplasmic reticulum.

Cardiac sarcoplasmic reticulum (CSR), isolated from dog hearts, was shown to be asymmetric in the distribution of phospholipids across the CSR bilayer. Phosphatidylethanolamine was mostly resident in the outer leaflet, phosphatidylcholine was equally distributed across both monolayers and phosphatidylserine was found primarily in the inner monolayer. This distribution of headgroups is similar to that found in fast skeletal muscle sarcoplasmic reticulum (SSR); however, the asymmetry in CSR is not as striking as that in SSR. Phospholipids retained by the CSR calcium pump protein (CaATPase) after detergent "stripping" were similar to those intimate to the SSR CaATPase, although the percentages of unsaturated phospholipids and plasmalogenic phospholipids are not as great as in the skeletal system. Lipids associated with the CSR CaATPase following DFDNB cross-linking showed a preference for retention of the aminophospholipids, again similar to the SSR CaATPase. Because the nonrandom distribution of membrane lipids modifies SSR function, it is likely these membrane lipids impact in situ the function of the CSR.

Animals↗
PubMed1997

The age-associated alterations in late diastolic function in mice are improved by caloric restriction.

Caloric restriction reduces the magnitude of many age-related changes in rodents. Cardiac function is altered with senescence in mice, rats, and healthy humans. We examined the effects of life-long caloric restriction on diastolic and systolic cardiac function in situ using Doppler techniques in ad libitum-fed 30- to 32-month-old (AL) and calorically restricted (CR) 32- to 35-month-old female B6D2-F1 hybrid mice. The heart weight to body weight ratio was similar in AL (5.74 +/- .24 mg/g) and CR (5.68 +/- .20 mg/g) mice. Two systolic functional parameters known to decrease with age in both humans and mice, peak aortic velocity and aortic acceleration, were unchanged by CR compared to AL. In contrast, diastolic function was altered by caloric restriction. Although left ventricular peak early filling velocity (E) was not different between CR and AL, peak atrial filling velocity (A) was 50% lower in CR compared to AL (p < .001). The ratio of early diastolic filling to atrial filling (E/A ratio) was 64% higher in the CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The fraction of ventricular filling due to atrial systole, the atrial filling fraction, was also reduced in CR (.21 +/- .04) compared to AL (.36 +/- .02; p = .007). These changes occurred in CR without alteration in E deceleration time, which is consistent with improved diastolic function in CR. Through mechanisms that remain unknown, lifelong caloric restriction may prevent the age-related impairments in late diastolic function but does not alter the impairments in systolic or early diastolic cardiac function.

Aging↗
PubMed1997

Noninvasive determination of pulse-wave velocity in mice.

Some transgenic mice have abnormal vascular function, but arterial geometry and dynamics are difficult to evaluate. To examine whether ultrasonic velocimetry could be used to determine arterial pulse-wave velocity (PWV) in mice, a custom-made 20-MHz pulsed Doppler instrument was used to obtain blood flow velocity signals from the aortic arch and the abdominal aorta 4 cm downstream. The upstroke (foot) of the velocity wave was timed at each site with respect to the R wave of the electrocardiogram, and PWV was calculated by dividing the separation distance by the difference in R-foot times. Doppler determinations were compared with invasive tonometry, and PWV was altered pharmacologically. It was found that the upstrokes of pressure (by tonometry) and velocity were coincident (+/-1 ms) and that PWV could be calculated by either method on exposed vessels. With the use of Doppler methods, pulse transit time was determined noninvasively with +/-1-ms resolution in 140 of 142 attempts in 82 mice. The calculated PWV in mice ranged from 220 to 850 cm/s with vasodilating anesthetics producing the low values and vasoconstricting agents producing the higher values. Thus PWV can be determined noninvasively in mice, is similar to that in other mammals, and responds as expected to vasoactive agents.

Animals↗
PubMed1997

Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium.

Tumor necrosis factor-alpha (TNF-alpha) mRNA and protein biosynthesis were examined in adult feline myocardium in the presence and absence of superimposed hemodynamic pressure overloading. A brief period of hemodynamic pressure overloading ex vivo resulted in de novo TNF-alpha mRNA expression within 30 minutes and de novo TNF-alpha protein production within 60 minutes; neither TNF-alpha mRNA nor protein was detected in hearts perfused at normal perfusion pressures. Moreover, TNF-alpha mRNA and protein biosynthesis were observed in myocyte and nonmyocyte cell types in the pressure-overloaded hearts. To determine whether a simple passive stretch of the myocardium was a sufficient stimulus for TNF-alpha biosynthesis, we examined TNF-alpha mRNA expression in stretched and unstretched papillary muscles. This study showed that myocardial stretch was a sufficient stimulus for the induction of TNF-alpha mRNA biosynthesis. The functional significance of the intramyocardial production of TNF-alpha was determined by examining cell motion in isolated contracting cardiac myocytes treated with superfusates from pressure-overloaded and control hearts. These studies showed that cell motion was depressed in myocytes treated with superfusates from the pressure-overloaded hearts but was normal with the superfusates from the control hearts. Finally, hemodynamic pressure overloading in vivo under physiological conditions was also shown to result in de novo intramyocardial TNF-alpha mRNA biosynthesis. In conclusion, this study constitutes the initial demonstration that the adult mammalian myocardium elaborates biologically active TNF-alpha, both ex vivo and in vivo, in response to hemodynamic pressure overloading.

Animals↗
PubMed1996

Noninvasive indexes of cardiac systolic and diastolic function in hyperthyroid and senescent mouse.

The mouse is a common model for transgenic manipulation, however, their small size has made hemodynamic study difficult. A noninvasive 10-MHz pulsed Doppler probe was used to measure aortic and mitral flow velocities in anesthetized, intact mice to study the effects of aging and hypethyroidism (induced by thyroxine) one systolic and diastolic cardiac function. In 10 hyperthyroid mice peak aortic velocity (PAV, an index of systolic function) was 34% higher than in 10 control mice (108 +/- 2 vs. 80 +/- 3 cm/s, P < 0.05). The ratio of early to late mitral filling velocity (E/A ratio, an index of diastolic function) was 47% higher (5.6 +/- 0.8 vs. 3.8 +/- 0.2, P < 0.05) in the hyperthyroid mice. In six old (30 mo) mice PAV was similar to eight young (4 mo) mice (73 +/- 3 vs. 75 +/- 3 cm/s), but the E/A ratio was 59% lower (1.8 +/- 0.3 vs. 4.4 +/- 0.4, P < 0.05). Despite a wide range of observed heart rates, the systolic and diastolic parameters of the groups were clearly separated. We conclude that cardiac systolic and diastolic function in mice, measured by pulsed Doppler ultrasound, are similar to larger species both in magnitude and in their response to hyperthyroidism and aging.

Aging↗
PubMed1996

SERCA2a and mitochondrial cytochrome oxidase expression are increased in hearts of exercise-trained old rats.

Aging of rats results in slower activities of calcium transport by cardiac calcium adenosinetriphosphatase (ATPase) of the sarcoplasmic reticulum (SR) and mitochondrial cytochrome oxidase (COX). These enzyme activities are faster after exercise training of previously sedentary old rats. Our purpose was to determine whether the expression of the genes encoding SR calcium ATPase (SERCA2a) or COX is altered by exercise training. Old (24-mo-old) male Fischer 344 rats were assigned to SO (sedentary old) or EO (exercised old) groups and compared with younger (12-mo-old) sedentary rats (SM). EO rats were trained on a treadmill for 8-10 wk. SERCA2a and COX mRNAs were lower (P < 0.05) in SO compared with SM and EO, whereas glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cardiac alpha-actin mRNAs were similar across groups. The immunoreactive protein contents of cardiac calcium ATPase, cytochrome c, sarcomeric actin, and GAPDH followed the changes, when observed, in mRNA contents. Thus pretranslational mechanisms may be modified in some genes during aging and exercise training of previously sedentary old rats.

Aging↗
PubMed1996

Exercise training improves lusitropy by isoproterenol in papillary muscles from aged rats.

Aging is associated with a decreased cardiac responsiveness to beta-adrenergic stimulation. We examined the effect of endurance exercise training of old Fischer 344 male rates on beta-adrenergic stimulation of the function of isolated left ventricular papillary muscle. Three groups were examined: sedentary mature (SM; 12-mo old), sedentary old (SO; 23-24 mo old), and exercised old (EO; 23-24 mo old) that were treadmill trained for 4-8 wk. The isometric contractile properties were studied at 0.2 Hz and 0.75 mM calcium. Without beta-adrenergic stimulation, there were no group differences for peak tension, maximum rate of tension development (+dP/dt), or maximum rate of tension dissipation (-dP/dt). The time to peak tension was longer (P < 0.05) for both EO and SO than for SM rats. Half relaxation time (RT1/2) was prolonged (P < 0.05) for SO compared with SM and EO (which did not differ). The three groups did not differ in the beta-adrenergic stimulation by isoproterenol of peak tension, -dP/dt, time to peak tension, or contraction duration. The inotropic response (+dP/dt) of SM was greater (P < 0.05) than that in SO or EO rats (which did not differ); however, the lusitropic response (RT1/2) was lesser (P < 0.05) in SO than in SM or EO rats (which did not differ). Thus exercise training of old rats improved the lusitropic response to isoproterenol without altering the age-associated impairment in inotropic response.

Adrenergic beta-Agonists↗
PubMed1994

Estimation of severity of illness with APACHE II: age-related implications in cardiac arrest outcomes.

The ability to predict outcomes of cardiac arrest before starting cardiopulmonary resuscitation (CPR) would be useful for discussions of resuscitation with elders and their families. We thought CPR outcome might be dependent on the severity of pre-existing illnesses. The APACHE II is a severity-of-illness (SOI) scale based, in part, on physiologic parameters whereby points are given for degree of deviation from normal. Additionally, up to six points are given for increased age. We hypothesized that (1) patients with the highest APACHE II would be least likely to survive, and (2) because of the blunted physiologic responsiveness, the APACHE II would underestimate the SOI of elderly patients who were sufficiently ill to have a cardiac arrest. A retrospective study of 172 arrests was carried out to evaluate these hypotheses. For the young cohort (n = 126; age, < 70; mean age, 59 +/- 8), mean admission APACHE II was 16.5 +/- 7.9 and pre-arrest APACHE II regression analysis.2+ carried out with both APACHE II scores and factors previously correlated with CPR outcome. Witnessed arrests and those requiring a low number of medications were most likely to result in immediate success (restoration of blood pressure) and in a live discharge. APACHE II score (24 h pre-arrest) was associated with live discharge in the regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗