Aims: 

So far, the cardiovascular function of the angiotensin II type-2 receptor (AT2) interacting protein (ATIP1) remained unknown. In this study, we used ATIP1 knockout mice to gain insight into the role of ATIP1 in anti-hypertrophic pathways.

Methods and results: 

Northern blot, RT-PCR, Western blot, and X-Gal expression studies revealed high levels of ATIP1 in the heart. Using confocal laser scanning microscopy, we detected a sarcolemmal localization of ATIP1 in cardiomyocytes. Our ATIP1-KO mice develop a spontaneous cardiac hypertrophy with a significantly increased heart/body weight ratio, enlarged cardiomyocyte diameter, and two-fold up-regulated myocardial fibrosis. In contrast, no significant differences in blood pressure were observed. After chronic angiotensin II (Ang II) infusion, invasive hemodynamic assessment of left ventricular function revealed that maximum volume, end-diastolic volume, and cardiac output were significantly reduced in ATIP1-KO animals. Functional measurements of isolated cardiomyocytes revealed slightly increased cell contractility in ATIP1-KO mice. Treatment with Ang II resulted in increased fractional shortening in WT but surprisingly decreased shortening in ATIP1-KO, accompanied by accelerated cell relaxation in WT, which was absent in ATIP1-KO cells. Treatment of cardiomyocytes with the AT2-agonist CGP42112A resulted in increased shortening in WT cells, again not affected in ATIP1-KO cells. Relaxation was expedited in WT by CGP42112A but almost unchanged in ATIP1-KO cells.

Conclusions: 

We here show for the first time that ATIP1-deficiency results in spontaneous cardiac hypertrophy in vivo and hypothesize that impaired angiotensin II type 2 receptor signalling and subsequently altered excitation-contraction coupling causes this cardiac dysfunction.