Investigation of the pathomechanism of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning in a rat model of chronic kidney disease
Chronic kidney disease (CKD) is a public health problem affecting 1 of 10 people worldwide. Interestingly, approximately 60% of patients are women in the early stages of CKD. A common cardiovascular complication of CKD is uremic cardiomyopathy, most characterized by left ventricular hypertrophy (LVH...
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| Dokumentumtípus: | Disszertáció |
| Megjelent: |
2023-04-27
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| doi: | 10.14232/phd.11611 |
| mtmt: | 34126375 |
| Online Access: | http://doktori.ek.szte.hu/11611 |
| LEADER | 05550nta a2200265 i 4500 | ||
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| 001 | dokt11611 | ||
| 005 | 20230905131235.0 | ||
| 008 | 230216s2023 hu om 0|| eng d | ||
| 024 | 7 | |a 10.14232/phd.11611 |2 doi | |
| 024 | 7 | |a 34126375 |2 mtmt | |
| 040 | |a SZTE Doktori Repozitórium |b hun | ||
| 041 | |a eng | ||
| 100 | 1 | |a Márványkövi Fanni Magdolna | |
| 245 | 1 | 0 | |a Investigation of the pathomechanism of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning in a rat model of chronic kidney disease |h [elektronikus dokumentum] / |c Márványkövi Fanni Magdolna |
| 246 | 1 | 0 | |a Az urémiás kardiomiopátia és a szív iszkémiás prekondícionálhatóságának vizsgálata krónikus veseelégtelenségben patkány modellben |h [elektronikus dokumentum] |
| 260 | |c 2023-04-27 | ||
| 502 | |a Disszertacio | ||
| 520 | 3 | |a Chronic kidney disease (CKD) is a public health problem affecting 1 of 10 people worldwide. Interestingly, approximately 60% of patients are women in the early stages of CKD. A common cardiovascular complication of CKD is uremic cardiomyopathy, most characterized by left ventricular hypertrophy (LVH) and fibrosis, ultimately leading to heart failure (HF). Moreover, uremic cardiomyopathy enhances the susceptibility of the heart to acute myocardial infarction (AMI). However, the precise molecular mechanisms and the role of sex-based differences in the development of uremic cardiomyopathy and AMI in CKD are still unclear. Therefore, novel therapeutic strategies that alleviate the severity of uremic cardiomyopathy and AMI in CKD are urgently needed. MicroRNA-212 (miR-212) has been demonstrated previously to be a crucial regulator of pathologic LVH in pressure-overload-induced HF via regulating the forkhead box O3 (FOXO3)/calcineurin/nuclear factor of activated T-cells (NFAT) pathway. Here we aimed to investigate whether i) miR-212 and its selected hypertrophy- and fibrosis-associated targets play a role in the development of uremic cardiomyopathy, ii) the influence of sex on the severity of uremic cardiomyopathy and AMI, as well as the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD. CKD was induced by 5/6 nephrectomy in male and female Wistar rats. Serum and urine laboratory parameters were measured to verify the development of CKD 8 or 9 weeks after the operations. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular (LV) samples were collected for RT-qPCR, Western blot, and ELISA measurements. The LV expressions of miR-212 and its LVH and fibrosis-associated selected targets, including FOXO3, AKT, and ERK1/2, were measured only in males by RT-qPCR and/or Western blot. In a subgroup of animals, hearts were perfused according to Langendorf and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE. Then the infarct size or phosphorylated (p) and total forms of proteins related to the cardioprotective RISK (AKT, ERK1/2) and SAFE (STAT3) pathways were measured in the myocardial samples by Western blot. The severity of CKD was similar in males and females based on serum urea and creatinine levels. In CKD, diastolic dysfunction developed with preserved ejection fraction and increased A-type natriuretic peptide (ANP) levels in both sexes; however, males developed more severe LVH than females. Moreover, histology showed the development of marked cardiac fibrosis only in CKD in males. The miR-212 was significantly overexpressed in the LV samples in CKD in males. However, the LV expression of FOXO3, AMPK, and ERK1/2 failed to change significantly at the mRNA or protein level. Interestingly, only the LV pAKT/AKT ratio was significantly increased in males in CKD. Females had significantly smaller infarct sizes both in the sham and CKD groups compared to males. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the pSTAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. The groups had no significant differences in pAKT/AKT and pERK1/2 / ERK1/2 ratios. In summary, cardiac overexpression of miR-212 in CKD failed to affect its previously implicated hypertrophy- and fibrosis-associated downstream targets in males. Thus, the molecular mechanism of the development of LVH in CKD seems to be independent of the FOXO3, ERK1/2, and AMPK in our model. The infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats and the smaller infarct size in females. Further research is needed to identify crucial molecular mechanisms in the development of uremic cardiomyopathy and the cardioprotective effects of IPRE in CKD. | |
| 650 | 4 | |a elméleti orvostudományok | |
| 650 | 4 | |a Orvos- és egészségtudomány | |
| 700 | 1 | |a Sárközy Márta Juianna |e ths | |
| 856 | 4 | 0 | |u https://doktori.bibl.u-szeged.hu/id/eprint/11611/1/Dr_Marvanykovi_Fanni_disszertacio.pdf |z Dokumentum-elérés |
| 856 | 4 | 0 | |u https://doktori.bibl.u-szeged.hu/id/eprint/11611/2/Dr_Marvanykovi_Fanni_angol_tezisfuzet.pdf |z Dokumentum-elérés |
| 856 | 4 | 0 | |u https://doktori.bibl.u-szeged.hu/id/eprint/11611/3/Dr_Marvanykovi_Fanni_magyar_tezisfuzet.pdf |z Dokumentum-elérés |
| 856 | 4 | 0 | |u https://doktori.bibl.u-szeged.hu/id/eprint/11611/7/PhD%20v%C3%A9d%C3%A9s%20megh%C3%ADv%C3%B3%20Dr.%20M%C3%A1rv%C3%A1nyk%C3%B6vi%20Fanni%20Magdolna.pdf |z Dokumentum-elérés |