Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation

Abstract

Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (Scd1), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of Scd1/SCD in heart failure is not clear, we investigated the impact of cardiac SCD upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of SCD. Echocardiographic examination showed that 4.9-fold-increased SCD levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-SCD mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-SCD mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-SCD hearts was significantly up-regulated. In transfected HEK cells, the expression of SCD increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that SCD promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein.

Comparison of blood leptin and vitamin E and blood and adipose fatty acid compositions in wild and captive populations of critically endangered Vancouver Island marmots (Marmota vancouverensis)

“…In Arctic ground squirrels ( Urocitellus parryii ) and Crossley's dwarf‐lemurs ( Cheirogaleus crossleyi ), fat‐storing hibernators with significantly different ecology, SCD activity is upregulated during fattening, in preparation for hibernation (Faherty et al, 2018). In mice models, SCD has been found to promote cardiac dysfunction via accumulation of cardiotoxic saturated lipids (Abd Alla et al, 2021). SCD activity assessment warrants further investigation throughout the yearly cycle of captive VIMs.…”

Role of Stearoyl-CoA Desaturase 1 in Cardiovascular Physiology

“…SCD1 is elevated in the heart in patients with diabetes and heart failure [ 35 , 38 ]. Scd1 mRNA levels are unchanged or reduced in hypertrophied hearts but are elevated at the onset of heart failure in various mouse models [ 38 , 39 , 40 , 41 ]. Scd1 expression also increases in the rat heart after a high-sucrose diet but without the onset of cardiac symptoms [ 35 ].…”

“…Scd1 overexpression stimulates de novo lipogenesis via the upregulation of FAS and leads to cardiac steatosis with greater SFA accumulation. Additionally, Scd1 overexpression causes upregulation of the angiotensin II receptor, AT1, which may be an additional pathogenic factor [ 39 ].…”

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

“…Some of those genes, which are specifically induced upon Pparg dephosphorylation on serine-273, are adiponectin (Adipoq), the lipid droplet associated cell death-inducing DFFA-like effector protein c (Cidec), resistin (Retn) and the mitochondrial brown fat uncoupling protein 1 (Ucp1) [ 120 ]. These Pparg target genes were induced in vivo by transgenic RKIP expression or by treatment with the heart failure-promoting Pparg agonist, rosiglitazone [ 21 , 22 , 121 ].…”

“…Transcriptome profiling documented increased fibrosis marker genes in Tg-RKIP hearts, i.e., Col1a1 and Col1a2 (collagen type I alpha 1 and 2 chain), Col3a1 (collagen type III alpha 1 chain), Ccn2 (cellular communication network factor 2; Ctgf ) and Fn1 (fibronectin 1) ( Figure 5 b). All of these genes are upregulated by enhanced AGTR1-Agtr1 stimulation [ 121 , 135 , 136 , 137 ]. Myocardial fibrosis was confirmed by picrosirius red staining of heart specimens from Tg-RKIP mice ( Figure 5 c and Reference [ 22 ]).…”