Deficiency of Pdk1 drives heart failure by impairing taurine homeostasis through Slc6a6

Abstract

Abstract3‐Phosphoinositide‐dependent protein kinase‐1 (Pdk1) as a serine/threonine protein kinase plays a critical role in multiple signaling pathways. Analysis of the gene expression omnibus database showed that Pdk1 was significantly downregulated in patients with heart diseases. Gene set enrichment analysis of the proteomics dataset identified apoptotic‐ and metabolism‐related signaling pathways directly targeted by Pdk1. Previously, our research indicated that Pdk1 deletion‐induced metabolic changes might be involved in the pathogenesis of heart failure; however, the underlying mechanism remains elusive. Here, we demonstrated that deficiency of Pdk1 resulted in apoptosis, oxidative damage, and disturbed metabolism, both in vivo and in vitro. Furthermore, profiling of metabonomics by 1H‐NMR demonstrated that taurine was the major differential metabolite in the heart of Pdk1‐knockout mice. Taurine treatment significantly reduced the reactive oxygen species production and apoptosis, improved cardiac function, and prolonged the survival time in Pdk1 deficient mice. Proteomic screening identified solute carrier family 6 member 6 (Slc6a6) as the downstream that altered taurine levels in Pdk1‐expression cells. Consistently, cellular apoptosis and oxidative damage were rescued by Slc6a6 in abnormal Pdk1 expression cells. These findings collectively suggest that Pdk1 deficiency induces heart failure via disturbances in taurine homeostasis, triggered by Slc6a6.

Functional Role of Taurine in Aging and Cardiovascular Health: An Updated Overview

“…The beneficial effects of taurine on Ca 2+ and sodium (Na + ) handling [89,90,[99][100][101][102][103], myocardial energetics [104,105], and cellular signaling pathways (including glucose transport, 3-phosphoinositide-dependent protein kinase-1, AKT, sirtuin 1 (SIRT1), FOXO3, p38, NFkappaB, and others) [106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] are thought to underlie its major cardioprotective effects. Other mechanisms include the promotion of natriuresis and diuresis, most likely via an osmoregulatory activity in the kidney, a regulation of vasopressin release, and a modulation of the atrial natriuretic factor secretion [122][123][124][125].…”