SWAP70 Overexpression Protects Against Pathological Cardiac Hypertrophy in a TAK1‐Dependent Manner

Abstract

Background Pathological cardiac hypertrophy is regarded as a critical precursor and independent risk factor of heart failure, and its inhibition prevents the progression of heart failure. Switch‐associated protein 70 (SWAP70) is confirmed important in immunoregulation, cell maturation, and cell transformation. However, its role in pathological cardiac hypertrophy remains unclear. Methods and Results The effects of SWAP70 on pathological cardiac hypertrophy were investigated in Swap70 knockout mice and Swap70 overexpression/knockdown cardiomyocytes. Bioinformatic analysis combined with multiple molecular biological methodologies were adopted to elucidate the mechanisms underlying the effects of SWAP70 on pathological cardiac hypertrophy. Results showed that SWAP70 protein levels were significantly increased in failing human heart tissues, experimental transverse aortic constriction–induced mouse hypertrophic hearts, and phenylephrine‐stimulated isolated primary cardiomyocytes. Intriguingly, phenylephrine treatment decreased the lysosomal degradation of SWAP70 by disrupting the interaction of SWAP70 with granulin precursor. In vitro and in vivo experiments revealed that Swap70 knockdown/knockout accelerated the progression of pathological cardiac hypertrophy, while Swap70 overexpression restrained the cardiomyocyte hypertrophy. SWAP70 restrained the binding of transforming growth factor β‐activated kinase 1 (TAK1) and TAK1 binding protein 1, thus blocking the phosphorylation of TAK1 and downstream c‐Jun N‐terminal kinase/P38 signaling. TAK1 interacted with the N‐terminals (1–192) of SWAP70. Swap70 (193–585) overexpression failed to inhibit cardiac hypertrophy when the TAK1–SWAP70 interaction was disrupted. Either inhibiting the phosphorylation or suppressing the expression of TAK1 rescued the exaggerated cardiac hypertrophy induced by Swap70 knockdown. Conclusions SWAP70 suppressed the progression of cardiac hypertrophy, possibly by inhibiting the mitogen‐activated protein kinases signaling pathway in a TAK1‐dependent manner, and lysosomes are involved in the regulation of SWAP70 expression level.

Identification of Potential Therapeutic targets for Stroke and Its Subtypes by Integrating Proteomes and Genetics from Human Plasma

“…Studies have shown protein glycosylation may affect the occurrence of AIS by regulating the progression of atherosclerosis and AF. 42 SWAP70 is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes, its role in many diseases is not clear yet, however, studies showed that SWAP70 is a protective molecule that can suppress the progression of nonalcoholic fatty liver disease by inhibiting hepatic steatosis and inflammation, 43 and Pathological Cardiac Hypertrophy, et al 44 Both of which were associated with stroke occurrence. SWAP70 also organizes the actin cytoskeleton, which is crucial for phagocytosis.…”

Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis

“…NADH-cytochrome b5 reductase 2 (CYB5R2) can preserve SkM mitochondria function in aging mice 34 . FGFBP3 and switch-associated protein 70 (SWAP70) may protect against weight gain 35 and cardiac hypertrophy 36 , respectively. Finally, dual specificity protein phosphatase 13 isoform A (DUSP13A) is highly specific to SkM 37 , making it a potential novel muscle-specific marker for long-term exercise.…”