Büttner Petra, Werner Sarah, Böttner Julia, Ossmann Susann, Schwedhelm Edzard, Thiele Holger
Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany.
Department of Cardiac Surgery, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany.
Int J Mol Sci. 2023 Sep 30;24(19):14782. doi: 10.3390/ijms241914782.
A restoration of low homoarginine (hArg) levels in obese ZSF1 rats (O-ZSF1) before (S1-ZSF1) and after (S2-ZSF1) the manifestation of heart failure with preserved ejection fraction (HFpEF) did not affect the worsening of cardiac HFpEF characteristics. Here, potential regulation of key enzymes of arginine metabolism in other organs was analyzed. Arginase 2 (ARG2) was reduced >35% in the kidney and small intestine of hArg-supplemented rats compared to O-ZSF1. Glycine amidinotransferase (GATM) was 29% upregulated in the kidneys of S1-ZSF1. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) levels were reduced >50% in the livers of O-ZSF1 but restored in S2-ZSF1 compared to healthy rats (L-ZSF1). In the skeletal muscle, iNOS was lower in O-ZSF1 and further decreased in S1-ZSF1 and S2-ZSF1 compared to L-ZSF1. iNOS levels were lower in the liver of the S2-ZSF1 group but higher in the kidneys of S1-ZSF1 compared to L-ZSF1. Supplementation with hArg in an in vivo HFpEF model resulted in the inhibition of renal ARG2 and an increase in GATM expression. This supplementation might contribute to the stabilization of intestinal iNOS and ARG2 imbalances, thereby enhancing barrier function. Additionally, it may offer protective effects in skeletal muscle by downregulating iNOS. In the conceptualization of hArg supplementation studies, the current disease progression stage as well as organ-specific enzyme regulation should be considered.
在射血分数保留的心力衰竭（HFpEF）出现之前（S1-ZSF1）和之后（S2-ZSF1），恢复肥胖ZSF1大鼠（O-ZSF1）低高精氨酸（hArg）水平，并未影响心脏HFpEF特征的恶化。在此，分析了其他器官中精氨酸代谢关键酶的潜在调节情况。与O-ZSF1相比，补充hArg的大鼠肾脏和小肠中的精氨酸酶2（ARG2）减少了>35%。S1-ZSF1大鼠肾脏中的甘氨酸脒基转移酶（GATM）上调了29%。与健康大鼠（L-ZSF1）相比，O-ZSF1大鼠肝脏中的二甲基精氨酸二甲胺水解酶1（DDAH1）水平降低了>50%，但在S2-ZSF1中恢复。在骨骼肌中，与L-ZSF1相比，O-ZSF1中的诱导型一氧化氮合酶（iNOS）较低，在S1-ZSF1和S2-ZSF1中进一步降低。与L-ZSF1相比，S2-ZSF1组肝脏中的iNOS水平较低，但S1-ZSF大鼠肾脏中的iNOS水平较高。在体内HFpEF模型中补充hArg导致肾脏ARG2受到抑制，GATM表达增加。这种补充可能有助于稳定肠道iNOS和ARG2失衡，从而增强屏障功能。此外，它可能通过下调iNOS对骨骼肌起到保护作用。在hArg补充研究的概念化过程中，应考虑当前的疾病进展阶段以及器官特异性酶调节。
