Author + information
- Man Xu and
- Qizhu Tang
One novel contributor to maladaptive cardiac remodeling is excessive myocytes hypertrophic growth, during which mitogens and other stimuli activate cell cycle proteins and their specific inhibitors.Cdkn1α is an important member of the cyclin-dependent kinase inhibitor (CDKI) family, which plays a crucial regulative role in cell-cycle progression. It has been known that myocardial Cdkn1α is up regulated under stimuli, the intracellular signaling mechanisms underlying its effect remain poorly understood. Present study was to investigate a novel role of Cdkn1α in the regulation of pressure overload induced cardiac remodeling.
Mice with global deletion of Cdkn1α (Cdkn1α-/-) and their wild type (WT) littermates were subjected to chronic pressure overload via aortic banding (AB) or sham surgery. Cardiac function was assessed via echocardiogram and pulmonary hemodynamics 4 weeks post-operation. Left ventricular tissue was excised for testing of the hypertrophic magnitude, interstitial collagen volume, transcriptome variations and alterations in protein signaling pathways. Neonatal rat cardiomyocytes (NRCMs) transfected with ShDNA plasmid of pSi-Cdkn1α targeting Cdkn1α mRNA was primary cultured and stimulated with angiotensin II (Ang II) for further verification in vitro.
The up-regulated expression of Cdkn1α was observed after AB. Heart weight/body weight (HW/BW), parameters of left ventricular contractility, relaxation and compliance function showed that Cdkn1α-/- mice have limited myocyte hypertrophy, reduced fibrosis and preserved heart function compared with WT mice. Cdkn1α-/- mice revealed restricted expression of AB-forced pro-inflammatory cytokines and pro-apoptotic proteins. Phosphorylation in PI3K/AKT/FoxO3a signaling pathway was down-regulated in Cdkn1α-/- mice, and hence the abundance of FoxO3a nuclear translocation and the level of its downstream anti-apoptotic protein ARC was increased. Consistent with the in vivo results, with the downregulation of Cdkn1α by pSi-Cdkn1α, NRCMs were prevented from Ang II induced hypertrophy and apoptosis.
Cdkn1α knockout protects the heart from pressure overload induced cardiac remodeling through PI3K/AKT/FoxO3a pathway.