PKNs are required for cardiac hypertrophy induced by angiotensin II in mice

Abstract

Of the three PKN isoforms, only homozygous Pkn2 knockout in mice is embryonic lethal; mice with Pkn2 haploinsufficiency or Pkn1/3 double knockout (Pkn1/3DKO) have no overt abnormalities. In adult mice, Pkn1/2 are implicated in development of cardiac disease, but studies of Pkn3 in the heart are lacking. Our hypothesis was that a role for Pkn1/3 in adult hearts would be revealed by pathophysiological stress. Here, we report expression profiles of PKNs in cardiac cells, identifying PKN2 as the dominant isoform with expression of PKN3 largely restricted to endothelial/immune cells. To test the hypothesis, Pkn1/3DKO, heterozygous Pkn2 knockout (Pkn2Het) and wild-type mice were treated with 0.8 mg/kg/d AngII, and cardiac function/dimensions assessed using speckle-tracking echocardiography. Baseline assessment identified minor differences in the left ventricle (LV) basal region in Pkn2Het (not Pkn1/3DKO) vs wild-type mice. AngII induced similar increases in LV end diastolic mass (LVEDM) in wild-type and Pkn1/3DKO mice at 3 d. LVEDM increased further in wild-type mice by 7d, but the initial response in Pkn1/3DKO mice was lost whilst stroke volume and cardiac output declined. Thus, hypertrophy was initiated in Pkn1/3DKO mouse hearts but not sustained. AngII increased cardiac fibrosis in wild-type mice together with mRNAs for cardiomyocyte hypertrophy and matrix proteins; this was suppressed in Pkn1/3DKO mice. Changes in expression of mRNA markers for cardiac non-myocytes suggested this was associated with vascular and immune cell dysfunction. In conclusion, Pkn2 does not substitute for Pkn1/3 in developing cardiac hypertrophy, and Pkn1/3 have an independent role in AngII-induced cardiac hypertrophy.