AKIP1, a Cardiac Hypertrophy Induced Protein that Stimulates Cardiomyocyte Growth via the Akt Pathway

Abstract

Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and β-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling.

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

“…6, A and F, and 7A). Hif-1␣ as a transcription factor is known to regulate the Postn expression (33), and meanwhile, both Hif-1␣ and Postn have been shown to positively activate Akt (23,35), which are consistent with our observations (Figs. 3, 4, 6, and 7).…”

“…Hypertrophy-To test whether miR-223-promoted hypertrophy is dependent on the activation of Akt, we pretreated neonatal cardiomyocytes with MK2206 (10 nM), a specific inhibitor of Akt (23). One hour later cells were transfected with Ad.miR-223 or Ad.GFP followed by 48-h culture.…”

Establishment of a prediction model of changing trends in cardiac hypertrophy disease based on microarray data screening

“…In the present study, the expression profiles of sham operated and ligated heart samples harvested from a Wistar rat were analyzed and 319, 44 and 57 DEGs were subsequently identified in the D1, D6 and D42 groups, respectively. AKIP1 , ANKRD23 , LTBP2 , TGF-β2 and TNFRSF12A were identified as common DEGs among the three groups, and their association with cardiac hypertrophy has previously been demonstrated ( 34 – 37 ). AKIP1 was identified as a key regulator of heart function via the cAMP-dependent protein kinase signaling pathway ( 38 ).…”

Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling

“…However, relatively little information is available regarding its function and intracellular signaling pathways in cardiovascular system. Accumulating evidence indicates that tumor suppressors can either positively or negatively modulate the cardiac hypertrophy [31,32]. In the first set of experiments, we screened mRNA and protein expression profile of ING3 in various tissues of rats, and found ING3 is highly expressed in the heart, suggesting that this gene may play a role in heart physiology and pathology.…”