Purpose Some protein kinases are regulated in STRIPAK complexes, with striatin (STRN) forming a scaffold. STRN mutations are associated with hypertension in humans and decreased expression of STRN causes arrhythmias and cardiomyopathy in dogs. Because striatin binds Ca2+-calmodulin, it was thought to participate in Ca2+-dependent signalling, but it is now recognised as regulatory B subunits of protein phosphatase PP2A. Thus, striatin holds the kinase in proximity to PP2A, maintaining it in an inactive state. Global striatin knockout is embryonic lethal in mice, but heterozygotes are viable and fertile. Our hypothesis is that heterozygote deletion of striatin will be detrimental to cardiac function in the context of hypertension.
Methods Cardiac function was assessed by echocardiography using a Vevo 2100 system. M-mode images of the short axis view were used for analysis of cardiac dimensions and ventricular function. Pulse-wave analysis of aortic flow was also performed. Following two baseline measurements, Strn ± mice (10–12 weeks) were infused with the pro-hypertensive hormone angiotension II (AngII; 0.8 mg/kg/day; n=5) via osmotic minipumps for 24 hour. Cardiac function and aortic flow was measured and normalised to the mean of the baseline values.
Results Compared to baseline, heart rates were elevated by 18%, whilst ejection fraction was reduced to 61% of baseline. Cardiac output was relatively preserved (87% of baseline). The internal left ventricular (LV) diameter was increased to some extent, but systolic function was severely compromised. Posterior wall thickness during systole was reduced to 79% of baseline measurements and LV internal diameter was increased by 23% giving a calculated increase in systolic volume of 67%.
Conclusions STRN plays an important role in maintaining systolic function during hypertension. Thus, the protein kinases that are regulated in striatin complexes must be significant regulators of cardiac contractility.
- heart failure
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