releases, which, in turn, activate ACs. This feed forward "fail safe" system, kept in check by a high basal phosphodiesterase activity, is central to the generation of normal rhythmic, spontaneous action potentials by pacemaker cells.Numerous studies over the past decade have indicated that intracellular Ca 2ϩ release is a key feature of normal cardiac pacemaker cell automaticity (1). More recently it has been demonstrated that the basal level of global cAMP in rabbit sinoatrial nodal cells (SANC) 3 exceeds that in ventricular myocytes (2).The high basal cAMP in SANC mediates robust basal protein kinase A (PKA)-dependent phosphorylation of specific surface membrane ion channels and Ca 2ϩ cycling proteins, which regulates the periodicity and amplitude of spontaneous, sarcoplasmic reticulum generated, local Ca 2ϩ releases in the absence of cell Ca 2ϩ overload (2). Local Ca 2ϩ releases emanate from ryanodine receptors of sarcoplasmic reticulum that lies beneath the sarcolemma (10 -15 nm), near the Na/Ca exchanger (NCX) proteins (3). Local Ca 2ϩ releases occur mainly during the late part of the spontaneous diastolic depolarization and activate an inward NCX current (4 -7). This imparts an exponential character to the late diastolic depolarization (5,8,9), facilitating the achievement of the threshold for opening of L-type Ca 2ϩ channels, which generate the rapid upstroke of the subsequent action potential (AP). Thus, cAMP-mediated, PKA-dependent phosphorylation of surface membrane ion channels and SR Ca 2ϩ cycling proteins control the SANC basal spontaneous rhythmic firing (2).The mechanisms that underlie a high basal cAMP in SANC are unknown. The failure of  1 or  2 adrenergic receptor (-AR) inverse agonists to alter the spontaneous, basal SANC firing rate indicates that high levels of cAMP are not due to constitutively active -ARs (2). Although a reduction in phosphodiesterase (PDE) activity could, in part, account for elevated cAMP levels in SANC, recent evidence suggests that basal PDE activity of SANC is not reduced, but rather, appears to be elevated (10). Moreover, inhibition of basal adenylyl cyclase (AC) activity in SANC substantially reduces cAMP and cAMP-mediated, PKA-dependent phosphorylation of phospholamban (2) suggesting a high constitutive (basal) level of AC activity. Whereas there is some evidence to indicate that SANC harbor Ca 2ϩ -activated AC isoforms (11, 12), direct evidence for Ca 2ϩ activation of AC activity, and the specific cell microdomains in which this may occur, are lacking. Using multiple approaches we show that both Ca 2ϩ -regulated ACs reside in lipid microdomains and that Ca 2ϩ activation of AC activity occurs within these domains.
Heart failure (HF) is the end result of progressive and diverse biological adaptations within the diseased myocardium. We used cDNA microarrays and quantitative PCR to examine the transcriptomes of 38 left ventricles from failing and nonfailing human myocardium. After identification of a pool of putative HF-responsive candidate genes by microarrays on seven nonfailing and eight failing hearts, we used quantitative PCR and a general linear statistical model in a larger sample set (n ؍ 34) to validate and examine the role of contributing biological variables (age and sex). We find that most HF-candidate genes (transcription factors, Cebpb, Npat; signaling molecules, Map2k3, Map4k5; extracellular matrix proteins, Lum, Cola1; and metabolic enzymes, Mars) demonstrated significant changes in gene expression; however, the majority of differences among samples depended on variables such as sex and age, and not on HF alone. Some HF-responsive gene products also demonstrated highly significant changes in expression as a function of age and͞or sex, but independent of HF (Ngp1, Cd163, and Npat). These results emphasize the need to account for biological variables (HF, sex and age interactions) to elucidate genomic correlates that trigger molecular pathways responsible for the progression of HF syndromes.
Cardiovascular diseases (e.g., vascular diseases, strokes, heart failure) reach epidemic proportions in the elderly and are the primary limits to survival in man. Age-associated changes in heart structure and function represent the major risk factors in heart failure (HF) syndromes and are associated with altered patterns of gene expression that can generally be seen as relative changes in the abundance of gene transcripts. An understanding of the molecular mechanisms underlying these changes should be tantamount to defining a genetic basis for aging; however, the analysis of processes as complicated as aging requires an accounting of biological diversity. Until recently, most of the changes in transcript abundance were identified one at a time, but the advent of gene expression arrays has permitted rapid, large-scale expression profiling. This has provided information about the dynamics of total gene expression, which can be used to identify pathways and elucidate regulatory events that may be affected during senescence or in response to disease. Importantly, very large sample sizes or meta-analyses of studies of smaller sample sizes should be sufficient to account for the diversity of altered gene expression that directs alterations in specific molecular pathways, which underlie changes in cardiac structure and function in senescence and disease.
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