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Transcriptional analysis of caveolae-related transcripts in the ischaemic-intolerant ageing mouse heart

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  1. Tez No: 541889
  2. Yazar: CAN JUSTIN KIESSLING
  3. Danışmanlar: DOÇ. Dr. KEVIN J. ASHTON, DOÇ. Dr. JASON N. PEART
  4. Tez Türü: Doktora
  5. Konular: Biyoteknoloji, Biotechnology
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2016
  8. Dil: İngilizce
  9. Üniversite: Bond Unıversıty
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

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Özet (Çeviri)

Ischaemic heart disease (IHD) is the most prevalent of the cardiovascular diseases and the largest single leading cause of death in Australia and other Western nations. Currently, there are no effective treatments that salvage the ischaemic myocardium as well as limiting the deleterious effects of reperfusion. Cardioprotection is a promising novel therapeutic for the treatment of IHD as cardioprotective interventions have been shown to limit both ischaemic and reperfusion (I-R) injury. However, its clinical translation has been limited due to its poor efficacy in the aged heart. Cardioprotective interventions such as ischaemic preconditioning as well as numerous pharmacological approaches are reliant on the presence of caveolae and present a novel therapeutic target as enhanced expression of caveolae has been shown to be protective against variety of stressors such as I-R injury in the aged heart. The unique morphology of caveolae arise from the expression of its coat proteins belonging to those of caveolin, cavin and Popdc family of proteins with differential expression of these protein shown to result in tissue-specific formation of caveolae. Whilst the age-related expression of Caveolin-3 (Cav3) has been investigated in the hearts, the expression of other caveolae-related transcripts is largely uncharactiersed. Their involvement may help partially explain age-related changes in cardioprotection. To show this, we sought to characterise age-dependant expression of caveolins, cavins and Popdcs in the ageing normoxic and post-ischaemic Langendorff model using transcriptional and immunoblotting analysis. Most murine ageing studies have focused on the aged/senescent phenotype (>74-week old), which show the efficacy of cardioprotective interventions as well as I-R tolerance is lost when compared to young (8-16 week old) counterparts. Here we show that the loss of ischaemic tolerance is evident in male middle-aged mouse hearts (48-week old) as shown by enhanced LDH release and post-ischaemic contractile dysfunction. Aged-related down-regulation of crucial caveolae transcripts Cav3, Cavin1 and Popdc1 was observed in middle-aged male hearts, which may partially explain the loss of protection in these hearts. We also characterised caveolar gene expression in the ageing female myocardium. As previous experimental and epidemiological studies in the ageing female hearts suggests they are more ischaemic tolerant. However, we did not observe this cardioprotective phenotype in ageing female hearts when compared to male counterparts. Coincident with the loss of cardioprotection in female hearts, the expression of Cav3 and Cavin1 showed similar patterns to male counterparts, although the relation between mRNA and protein was less consistent in females. We sought to further investigate the involvement of caveolae (specifically Cav3) in ischaemic tolerance by employing an RNAi cell culture model. Whilst this transfection rate was comparable to that of literature using chemical transfection methods, the degree of knockdown obtained with such rates is not associated with reliable repression of Cav3 mRNA. Thus, pharmacological disruption (MβCD) of caveolae was employed to show caveolae involvement in modifying ischaemic tolerance. MβCD-treatment following simulated ischaemia-reperfusion resulted in increased cell death when compared to non-treated simulated ischaemia-reperfused HL-1 cardiac cells. Recently, a novel type of small RNA molecules termed microRNAs (miRNAs) have emerged as important regulators of ageing, ischaemia-reperfusion injury and ischaemic conditioning. We sought to investigate the expression of several key miRNAs in the ageing male hearts, namely those implicated to have a role in ageing and ischaemia-reperfusion. Of the miRNAs associated with ageing, only miR-378 was differentially expressed in both the normoxic and post-ischaemic ageing hearts. Bioinformatic prediction was used to identify miRNA candidates targeting Cav3 and Cavin1 transcripts. No inverse-relationship was observed for miRNAs predicted to target Cav3 and Cavin1 in the ageing heart. Increasing evidence suggests that caveolae and their coat proteins are crucial contributors to the plasma membrane response. This is shown by the accumulation of caveolae-like vesicles near the sites of injury. Of the plasma membrane repair transcripts, only Anxa5 showed significant down-regulation with ageing in the normoxic hearts. There was also marked induction of proteases Trim54 and Calpain3, these may be responsible for the reduction of recovery observed in the young-adult and middle-aged hearts although this remains to be shown at the protein level. In conclusion, here we show significant age-related reductions in I-R tolerance in both male and female hearts, evident by 32-weeks of age (prior to 'middle-age'), with middle aged hearts exhibiting marked exaggeration of oncosis and contractile dysfunction. Age-dependent impairment of stress-tolerance was associated with significant baseline reductions in cardiac transcript for all three caveolins in male but not female tissue, which was conserved for Cav3 in post-ischaemic tissue. These data reveal age-dependent repression of transcript and protein for critical caveolar proteins (Cav3, Cavin1 and Popdc1) that are more pronounced in male hearts compared to female counterparts. Through mechanisms yet identified, age appears to suppress transcription and expression of multiple caveolar proteins relevant to cardiac stress responses, although female hearts exhibit lesser changes than males. Taken together, age-related down-regulation of caveolae which co-localise several crucial cardioprotective receptors and caveolar coat proteins which help target plasma membrane repair proteins to sites of injury may help partially explain reduced ischaemic tolerance in these hearts as well as reduced responsiveness to therapeutic intervention. Indeed, restoration of caveolae in the aged heart is associated with increased recovery and mechanisms leading to restoration of caveolae in the aged hearts have been suggested to be therapeutic for IHD.

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