The AngioTensin II type-2 receptor-Interacting Protein (ATIP-1) was originally described as mitochondrial protein exerting anti-proliferative effects, hence the second name Mitochondrial TUmor Suppressor 1 (MTUS1) but was also found to interact with the angiotensin II type-2 receptor (AT₂). In the latter context, ATIP-1 was described as a mediator of AT₂-dependent signalling pathways, which are regarded to act anti-hypertrophic in cardiac myocytes.

To clarify the physiological role of ATIP-1 in the cardiovascular system, we generated mice with a trapped Atip1 gene. Expression studies by Northern blot, RT-PCR, Western blot, and ex vivo X-Gal promoter studies revealed a surprisingly high promoter activity and expression level of ATIP-1 in the heart. Using confocal laser scanning microscopy, a plasma membrane-associated localisation of ATIP-1 in cardiac myocytes was detected, which is in sharp contrast to the previously proposed mitochondrial localisation. Localisation of ATIP-1 to the plasma membrane was supported by immunoprecipitation experiments, which confirmed a direct interaction of ATIP-1 and AT₂ in cardiac myocytes. Functionally, ATIP-1 knockout mice develop a spontaneous cardiac enlargement, demonstrated by an increased heart/body weight ratio of 6.4 x 10^-3 vs. 4.7 x 10^-3 of wild-type controls (n=16; p<0.05). Blood pressure measurements in conscious mice (tail cuff) did not provide significant differences between knockout mice and controls (SBP WT/KO 110/107,DBP WT/KO 70/68, MBP WT/KO 84/81 n=16). In summary, the Atip1 gene disruption results in spontaneous cardiac hypertrophy in vivo, underlining the importance of this ATIP-1/AT₂-dependend pathway in cardiac myocytes. Our findings in ATIP-1 knockout mice demonstrate for the first time a physiological function of ATIP-1 in the heart and support the hypothesis that AT₂-dependent signaling is anti-hypertrophic.