In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

Masternak, Michał M.; Bartke, Andrzej

doi:10.1016/j.exger.2010.02.009

Cited by 27 publications

(31 citation statements)

References 63 publications

(120 reference statements)

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“…Moreover, aortic VSMC-restricted IGFBP-4-overexpression models, even without changes in total body weight, have selectively increased the weight of the aorta, to which atherosclerotic lesions have to be related [149]. Compensatory increased substitute pathways of IGF-1 activation are also turned on in mice lacking the PAPP-A gene, thus confounding the comparison of the transgenic and wild-type animals [150]. Finally, as stated by the authors [148], control apoE-knockout mice had less lesion development than observed in previous studies, due to a genetic background less prone to atherosclerosis.…”

Section: From Risk Factors To Atherothrombosis Through Low Igf-1-medimentioning

confidence: 96%

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

et al. 2011

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IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti-thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti-thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine.

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Section: From Risk Factors To Atherothrombosis Through Low Igf-1-medimentioning

confidence: 96%

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

et al. 2011

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“…PAPPA2 is a metalloproteinase that regulates insulin-like growth factor bioavailability, and previous mouse knockout studies for PAPPA2 show growth retardation and ~30% extended life span (28). Unfortunately, we were unable to verify differential expression between offspring and spouses for PAPPA2 using RT-PCR despite using multiple probe sets and confirming that the RT-PCR assay conditions were successful when using placental tissue, where PAPPA2 is known to be expressed, as a positive control.…”

Section: Discussionmentioning

confidence: 56%

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

Yerges‐Armstrong

Chai

O’Connell

et al. 2016

GERONA

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Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4 × 10 −4 ) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80 kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2. Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates. Keywords: Longevity genetics-Gene expression-PAPSS2Life span is the result of a complicated interplay between genetic and environmental factors. Although much of the genetic research on aging has focused on predisposition of age-related diseases such as cardiovascular and Alzheimer's disease, compelling evidence from animal models and human studies supports the existence of genetic factors that enhance life span itself by influencing cellular aging (1-3).Studies of twins reared together and twins reared apart suggest that genetic factors explained ~30% of the variance in longevity (4,5), and heritability of life span in the Old Order Amish was previously estimated as ~25% (6). A stronger genetic influence on longevity has been reported for more extreme life-span phenotypes (eg, premature death or exceptional survival) than for life span in general (7,8). A study by Perls and colleagues demonstrated that the siblings of centenarians are 8-17 times more likely to survive to age 100 compared with other individuals from their birth cohorts (9). Ashkenazi parents of centenarians were approximately seven times more likely to live to age 90 (10), and the Leiden Longevity Study found that mortality rates in first-degree relatives of long-lived individuals were 30% lower compared with the general population (11). These studies support the concept that longevity is a familial trait likely to be inherited and demonstrate the potential utility of using family studies in identifying longevity assurance genes.

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“…It is difficult to evaluate IGF-I bioactivity in vivo . However, IGFBP-5 is an IGF-I responsive gene, and IGFBP-5 mRNA levels have been used as a surrogate marker for IGF receptor activation in several tissues in vivo (11, 14–19). Therefore, we measured IGFBP-5 mRNA in the tissues in Figures 1 and 2 (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, in this study we used a surrogate marker of PAPP-A regulation of IGF-I bioactivity, IGFBP-5 mRNA levels (11, 14–19). Changes in IGFBP-5 mRNA levels paralleled those of PAPP-A in kidney, bone, skeletal muscle and thymus of both male and female mice, supporting an IGF-dependent role for PAPP-A in these tissues.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

Harstad

Conover

2014

Experimental Gerontology

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Pregnancy-associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase that functions in many systems outside of pregnancy. Data in both humans and mice suggest a role for PAPP-A in aging and age-related diseases. However, our knowledge of tissue-specific PAPP-A expression and possible changes in this expression with age is limited. Thus, the aim of this study was to determine PAPP-A mRNA expression in multiple tissues with age in both male and female mice using real-time PCR. These included heart, liver, kidney, bone, fat, skeletal muscle, gonads, brain, thymus and spleen. In young mice, PAPP-A mRNA was expressed at relatively high levels in all tissues examined except for liver. The only difference in expression between males and females was seen in kidney, subcutaneous fat and gonads. The highest PAPP-A mRNA expression levels were found in visceral fat and these were 10-fold higher than in subcutaneous fat. PAPP-A expression significantly increased with age in kidney, brain and gonads. PAPP-A expression significantly deceased with age in bone and skeletal muscle. In the thymus, PAPP-A mRNA showed a biphasic response with age. There were no age-related changes in PAPP-A expression seen in any of the other tissues examined. Expression of IGFBP-5 mRNA, a marker of insulin-like growth factorI (IGF-I) bioactivity known to be regulated by PAPP-A, paralleled the changes in PAPP-A expression with age in kidney, bone, skeletal muscle and thymus. Thus, tissue-specific PAPP-A expression in mice is differentially affected during aging, and may regulate local IGF-I bioactivity in certain tissues.

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In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene

Cited by 27 publications

References 63 publications

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

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