Medar 2019 MiP2019
Mitochondrial dynamics modulate multiple mitochondrial functions critical for cardiac function, ranging from energy and reactive oxygen species production to Ca2+ homeostasis and cell death. The relevance of altered mitochondrial dynamics in aging-associated heart failure and cardiac hypertrophy is recognized.
In this study, we analyzed the effect of long-term treatment with sildenafil (inhibitor of phosphodiesterase 5) on age-associated changes in expression of main markers of mitochondrial dynamics (mitochondrial biogenesis, fission/fusion and mitophagy) in rat myocardium. Middle-aged (12 month-old) Wistar rats were treated orally for 6 months till old-age (18 months-old) with sildenafil (1.25 mg/kg body weight per day) while control group of rats received water.
RQPCR analysis revealed increased transcription of Ppargc1a (main regulator of mitochondrial biogenesis and function) in myocardium obtained from old compared to adult (3 month-old) rats, while sildenafil-treatment prevented age-associated increase of Ppargc1a. However, aging as well as sildenafil-treatment did not change expression patterns of its downstream genes Nrf1, Tfam and Nrf2. In high energy-demanding cardiomyocytes balance between mitochondrial fusion and fission is of crucial importance because imbalance causes cardiomyocyte dysfunction and death. Aging stimulate expression of main genes that constitute machinery promoting mitochondrial fusion (Mfn1, Mfn2 and Opa1) and possibly formation of enlarged mitochondria. This aging-induced stimulation of profusion genes was prevented by sildenafil-treatment. Aging interfered with mitochondrial quality control and increased transcription Pink1 (marker of mitophagy) while sildenafil-treatment normalized expression to level observed in adult rats.
Taking together, our results suggest that pharmacological targeting of cGMP-signaling could affect mitochondrial dynamics in myocardium during aging.
Labels: MiParea: mt-Biogenesis;mt-density, mt-Structure;fission;fusion, Pharmacology;toxicology Pathology: Aging;senescence
Organism: Rat Tissue;cell: Heart
Affiliations and support
- Lab Chronobiology Aging, Lab Reproductive Endocrinology Signaling, Centre Excellence CeRES, Fac Sciences, Univ Novi Sad, Novi Sad, Serbia. – [email protected]
- This work was supported by the grant no. 173057 and grant no. 451-0302807 Centre of Excellence CeRES from the Ministry of Education, Science and Technological Development, Republic of Serbia, as well as grant no. 2130 from the Autonomous Province of Vojvodina.