Background: Visceral adipose tissue derived serine protease inhibitor (vaspin), a secretory adipokine, was reported to play a protective role in insulin resistance. Recent studies have demonstrated that serum vaspin levels are downregulated in patients with coronary artery disease (CAD) and that vaspin has a protective effect on myocardial ischaemia/reperfusion injury (IRI) and atherosclerosis. However, whether vaspin exerts specific effects on pathological cardiac hypertrophy remains unknown.
Methods: Pathologic cardiac hypertrophy was induced in male C57BL/6J wild type (WT) and vaspin knockout (vaspin ko) mice. Buparlisib (PI3K inhibitor, 50 mg/kg), rapamycin (mTOR inhibitor, 20 mg/kg), or A 769662 (AMPK agonist, 30 mg/kg) wer e pre and co administered to vaspin ko mice daily for a period of 15 days. Induction of pathological cardiac hypertrophy was performed by the subcutaneous administration of isoproterenol (ISO) (5 mg/kg) into mice from the 7th to the 15th day. Cardiac hype rtrophy, fibrosis, and cardiac function were examined in these mice. Critical characteristics of senescence (senescence associated β galactosidase activity and expression of cyclin dependent kinase inhibitors) were examined in the cardiac hypertrophy model
Results: We provide the first evidence that the serum level of vaspin decreased during pathological cardiac hypertrophy; further, knocking out of vaspin resulted in markedly exaggerated cardiac h ypertrophy and fibrosis, and increased cardiomyocyte senesc senescence in mice treated with ISO. Conversely, the administration of exogenous ence in mice treated with ISO. Conversely, the administration of exogenous recombinant human vaspin in vitro protected myocardial cells against hypertrophy recombinant human vaspin in vitro protected myocardial cells against hypertrophy and senescence caused by ISO. and senescence caused by ISO. MechanisticallyMechanistically, PI3K, PI3K--AKTAKT--mTOR mTOR pathwaypathway--dependent activation of autophadependent activation of autophagic flux was involved in the protective gic flux was involved in the protective effects of vaspin toward cardiac hypertrophy.effects of vaspin toward cardiac hypertrophy.
Conclusion: Our results showed for the first time that vaspin functions as a critical Our results showed for the first time that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating regulator that alleviates pathological cardiac hypertrophy by regulating autophagyautophagy--ddependent myocardial senescence, which provides potential preventive and ependent myocardial senescence, which provides potential preventive and therapeutic targets for pathological cardiac hypertrophy.therapeutic targets for pathological cardiac hypertrophy.