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The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocytespecific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P < 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1<) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice. [ABSTRACT FROM AUTHOR]

Cardioprotective effects of anesthetic preconditioning and cyclosporine A (CsA) are lost with aging. To extend our previous work and address a possible mechanism underlying age-related differences, we investigated the role of oxidative stress in the aging heart by treating senescent animals with the oxygen free radical scavenger Tempol. Old male Fischer 344 rats (22-24 mo) were randomly assigned to control or Tempol treatment groups for 2 or 4 wk (T×2wk and T×4wk, respectively). Rats received isoflurane 30 min before ischemia-reperfusion injury or CsA just before reperfusion. Myocardial infarction sizes were significantly reduced by isoflurane or CsA in the aged rats treated with Tempol (T×4wk) compared with old control rats. In other experiments, young (4-6 mo) and old rats underwent either chronic Tempol or vehicle treatment, and the levels of myocardial protein oxidative damage, antioxidant enzymes, mitochondrial Ca2× uptake, cyclophilin D protein, and mitochondrial permeability transition pore opening times were measured. T×4wk significantly increased MnSOD enzyme activity, GSH-to-GSSH ratios, MnSOD protein level, mitochondrial Ca2×2+ uptake capacity, reduced protein nitrotyrosine levels, and normalized cyclophilin D protein expression in the aged rat heart. T×4wk also significantly prolonged mitochondrial permeability transition pore opening times induced by reactive oxygen species in old cardiomyocytes. Our studies demonstrate that 4 wk of Tempol pretreatment restores anesthetic preconditioning and cardioprotection by CsA in the old rat and that this is associated with decreased oxidative stress and improved mitochondrial function. Our results point to a new protective strategy for the ischemic myocardium in the high-risk older population. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein (MAP) kinase signaling pathways help to mediate the hypertrophic response of the pressure-loaded adult heart, although their importance in fetal myocardium is less known. The goal of this study was to determine the role the MAP kinase signaling pathways play in regulating the response of the fetal heart to a pressure load. Aortic (Ao) and pulmonary artery (PA) bands were placed in 132-day fetal sheep for 7 days. Protein levels of the total and active (phosphorylated) terminal MAP kinases extracellular signal-regulated kinase (ERK/P-ERK), c-Jun NH2-terminal kinase (JNK/P-JNK), and p38/P-p38 and the MAP kinase phosphatases MKP-1, MKP-2, and MKP-3 were made in the right and left ventricular (RV and LV) free walls. In both Ao- and PA-banded animals, total heart weight normalized to body weight was significantly increased, largely due to an increase in RV free wall mass in the Ao-banded animals and an increase in septal mass in the PA-banded fetuses. Total protein levels of the three terminal kinases and of P-ERK and P-JNK remained stable in both groups of banded animals. However, P-p38 was significantly increased in RV and LV of Ao- and PA-banded fetuses. Whereas MKP-1 and MKP-2 protein levels were unchanged following Ao- and PA-banding, MKP-3 protein levels were significantly increased in the RV of the PA-banded animals. These findings indicate that the MAP kinase signaling pathways are active in the fetal heart and help to modulate the response of prenatal myocardium to a pressure load. [ABSTRACT FROM AUTHOR]

Serum response factor (SRF) is an important transcription factor that may have a role in the maintenance of cardiac structure and function. The level of SRF mRNA expression increases ∼16% in the hearts of mice during adult aging. To model the effect of mild SRF elevation in the aging heart, transgenic mice with low levels of SRF overexpression were generated. By 6 mo of age, the transgenic mice had a 19% increase of heart-to-body weight ratio compared with nontransgenic mice. In addition, they had a 12% increase in myocyte size, a 6.7% increase in collagen deposition, and altered gene expression of a number of muscle-specific and cardiac genes. Doppler echocardiography revealed that these transgenic mice had increased left ventricular wall thickness and decreased left ventricular (LV) volumes, increased LV stiffness with 20% reduction in early diastolic LV filling (peak E), and 35% decline in peak E-to-peak A (late diastolic filling) ratio. The observed changes, especially those in the E/A ratio, are similar to those seen clinically in late life as a part of human adult myocardial aging. [ABSTRACT FROM AUTHOR]

Examines the role that mitochondria may play in influencing the apoptic process in vivo in the aging heart. Definition of aging and apoptosis; Measurement of isolated cardiac mitochondria and cytosol to determine whether or not the level of apoptosis changes with age; Release of cytochrome c release from the mitochondria and its use in determining the increase in apoptosis in the aging heart.

Presents a study which determined the role of growth hormone replacement in the reversal of age-related cardiac contractility and myofilament dysfunction. Methodology; Results; Discussion.

Presents a study which determined whether alpha adrenergic receptor-induced contraction is impaired in the aging rat heart. Role of protein kinase C in regulating the alpha adrenergic effects on cardiac contraction; Methodology; Results and discussion.

Presents a study which examined the effect of aging on whole cell membrane currents in ventricular myocytes isolated from young adult and aged rats. Aging-associated anatomical changes in humans and animals; Electrophysiological alterations due to decreased ventricular function; Discussion.

Presents information on a study which hypothesized that lusitropy is impaired in aging mouse hearts and correlates with an age-related decrease in cytosolic calcium removal. Materials and methods of the study; Results and discussion.

Tests the hypothesis that increased expression of beta-myosin heavy chain, as occurs in the normal aging process in the rodent heart, contributes to the prolongation of the twitch by depressing the kinetics of cross-bridge interaction. Rate of tension development and unloaded shortening velocity in chemically skinned myocardium; Calcium levels.

Provides information on a study regarding nonlinear dynamics of heartbeat aging. Methodology; Statistical analysis; Results.

Determines whether long-term food restriction enhances age-associated changes in the heart by studying various parameters of myocardial performance over a wide range of inotropic states. Age-related changes enhanced and attenuated by food restriction; Increased pressure development under low-calcium perfusate as one of the induced changes unrelated to age.

Examines the hypothesis that maturational changes in sheep heart are paralleled by alterations in the adenine nucleotide translocator (ANT), which are in turn related to changes in the expression of the gene. Methodology used in study; Why Northern blot analyses were performed; Details on maturation from fetal to mature; Indications of the respiratory control pattern in the newborn.

Investigates the effect of potassium, magnesium, and potassium-magnesium (K-Mg) cardioplegia on phosphocreatine (PCr), nucleoside triphosphate (NTP), and intracellular free magnesium (Mg) during normothermic global ischemia and reperfusion in the senescent myocardium. Methodology of the study; Results and conclusions of the study.

Determines the effects of aging and automonic input on interrelationships between respiratory and heart rate variability in the hear and lungs. Age-related changes in respiration; Influence of respiration on heart rate; Hear rate analysis; Findings of age-related differences.

Studies the effects of aging on atrioventricular (AV) nodal and right and left ventricular beta-adrenergic receptor characteristics in Fischer rat hearts using quantitative autoradiography. AV nodal beta-adrenergic receptor characteristics; Ventricular beta-adrenergic receptor characteristics; AV node volume.

Tests the hypothesis that opioid peptide production in the heart may increase with advancing age. Measurement of opioid peptide concentrations; Functional implications of research results to the aging heart.