Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Abstract

Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4–6 months), aged WT (24–26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4–6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9–Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

“…Besides, Sestrin2 knockout led to increased fibrogenesis and development of more severe pressure overload cardiac remodeling and hypertrophy in rats [107]. Sestrin2 knockout disrupted mitochondrial function of cardiomyocytes and was associated with decreased glucose oxidation; decreased PGC-1α and mitochondrial DNA; and elevated levels of 4-hydroxynonenal, a lipid peroxidation byproduct, in the rat model of pressure overload-mediated heart failure [107]. Sestrin2 knockout decreased autophagy and increased apoptotic cell death of cardiomyocytes, as well [107].…”

“…Sestrin2 knockout disrupted mitochondrial function of cardiomyocytes and was associated with decreased glucose oxidation; decreased PGC-1α and mitochondrial DNA; and elevated levels of 4-hydroxynonenal, a lipid peroxidation byproduct, in the rat model of pressure overload-mediated heart failure [107]. Sestrin2 knockout decreased autophagy and increased apoptotic cell death of cardiomyocytes, as well [107].…”

“…Furthermore, Sestrin2 protects against cardiac hypertrophy by inhibiting mTORC1. mTORC1 phosphorylates and negatively regulates ULK1/2 and other autophagy-related molecules to inhibit autophagy (Figure 1) [107][108][109][110]. Agerelated reduction in Sestrin2 has been proposed as a probable mechanism for cardiac dysfunction and remodeling in older age [109].…”

The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases

“…In rats, sestrin2 knockdown was reported to aggravate the cardiomyocyte hypertrophy induced by phenylephrine, and sestrin2 overexpression protected cardiomyocytes from phenylephrine-induced hypertrophy, suggesting a protective effect of sestrin2 against cardiomyocyte hypertrophy [ 36 ]. In addition, Quan et al reported that sestrin2 knockout mice had larger hearts and impaired cardiac function after aortic constriction for pressure overload [ 51 ]. Hypertension is the main pathological factor in the development of heart failure, and heart failure caused by hypertension is characterized by cardiac hypertrophy.…”

“…Hypertension is the main pathological factor in the development of heart failure, and heart failure caused by hypertension is characterized by cardiac hypertrophy. An adeno-associated virus delivery of sestrin2 rescued the sestrin2 expression, attenuated the activation of mTORC1 and increased the pressure overload tolerance in hearts [ 51 ]. These results indicate that sestrin2 inhibits myocardial hypertrophy by inhibiting the mTORC1 pathway, thereby regulating protein synthesis, metabolism, autophagy, and apoptosis.…”