ATIP1 Is a Suppressor of Cardiac Hypertrophy and Modulates AT2-Dependent Signaling in Cardiac Myocytes

So far, the molecular functions of the angiotensin-type-2 receptor (AT2) interacting protein (ATIP1) have remained unclear, although expression studies have revealed high levels of ATIP1 in the heart. To unravel its physiological function, we investigated ATIP1-KO mice. They develop a spontaneous cardiac hypertrophy with a significantly increased heart/bodyweight ratio, enlarged cardiomyocyte diameters, and augmented myocardial fibrosis. Hemodynamic measurements revealed an increased ejection fraction (EF) in untreated ATIP1-KO mice, and reduced end-systolic and end-diastolic volumes (ESV and EDV), which, in sum, reflect a compensated concentric cardiac hypertrophy. Importantly, no significant differences in blood pressure (BP) were observed. Chronic angiotensin II (AngII) infusion resulted in increases in BP and EF in ATIP1-KO and WT mice. Reductions in ESV and EDV occurred in both ATIP1-KO and WT but to a lesser extent in ATIP1-KOs. Isolated cardiomyocytes exhibited a significantly increased contractility in ATIP1-KO and accelerated Ca2+ decay. AngII treatment resulted in increased fractional shortening in WT but decreased shortening in ATIP1-KO, accompanied by accelerated cell relaxation in WT but absent effects on relaxation in ATIP1-KO cells. The AT2 agonist CGP42112A increased shortening in WT cardiomyocytes but, again, did not affect shortening in ATIP1-KO cells. Relaxation was accelerated by CGP42112A in WT but was unaffected in ATIP1-KO cells. We show that ATIP1 deficiency results in spontaneous cardiac hypertrophy in vivo and that ATIP1 is a downstream signal in the AT2 pathway regulating cell contractility. We hypothesize that the latter effect is because of a disinhibition of the AT1 pathway by impaired AT2 signaling.