Mechanism Of BCAA/mTORC1 Mediating Left Ventricular Remodeling In Spontaneously Hypertensive Rats

Objective: To investigate the progression of left ventricular remodeling in SHR mediated by BCAA regulating m TORC1 signaling pathway.Methods: Substances levels and energy metabolism in left ventricular tissues were monitored in SHR and WKY at age of 2 months,4 months,6months and 12 months,stimulating left ventricular remodeling in hypertensive heart disease,including:1)HTN without LVH;2)early stage of LVH;3)LVH completed;4)LVH with decreased contractile function.Furthermore,metabonomics and transcriptome were adopted to investigate the concentration and catabolism level of BCAA in left ventricular tissues at different stages.Meanwhile,the concentration of Ang II,a key factor of RAAS,influences the catabolic level of BCAA which regulates the m TORC1 signaling pathway to mediate the occurrence and progression of left ventricular remodeling.In vitro,H9C2 cells were used for a furthrer validation.Results: The levels of substances in SHR at different stages of left ventricular remodeling and and WKY were detected,and it was found that the most obvious change of substance content in SHR was at the onset of LVH,with an obvious accumulation of circulating BCAA and FFAs.Additionally,it was accompanied by decreased levels of GHb and INS,with an increased level of PDH activity in left ventricular tissue.Furthermore,analysis of targeted amino acid metabolomics showed that compared with WKY of the same age,the level of BCAA in left ventricular tissue began to accumulate at the onset of LVH(4 months of age)in SHR where valine was the first to accumulate.Transcriptional sequencing analysis showed that LVH formation in early SHR may be related to TCA,BCAA catabolic metabolism,m TOR signaling pathway,oxidative stress and autophagy levels,and the expression of BCKDK in left ventricular tissues was significantly stronger than that of WKY at age of 4 months.The structure and function of mitochondria and autophagy levels were detected.As reported,it was found that mitochondrial swelling and crista fracture appeard in early stage of LVH,which gradually became worse in the later stage.A decline in autophagy levels began at the age of 4 months.Further,BT2 increased the catablism of BCAA by inhibiting the expression of BCKDK in left ventricular tissue of early SHR.It was found that reduced levels of BCAA in left ventricular tissue could reduce left ventricular remodeling.The phosphorylation abundance of p70S6 K and total p70S6 K were detected,and BT2 could reduce the phosphorylation level of p70S6 K,and reduce mitochondrial swelling and crest fracture in SHR-BT2(5mg/kg)or SHR-BT2(10mg/kg)group,accompanied by an increase in autophagy level.In vitro,it showed that adding exogenous valine to H9C2 cardiomyocytes under Ang II could increase cardiomyocyte hypertrophy,ROS level,mitochondrial structure damage and reduced autophagy level.Otherwise,BT2 or Raptor si RNA reduced.At the same time,ROS content decreased cardiomyocyte are,with improved mitochondrial structure and increased autophagy level.Conclusion: During the progression of left ventricular remodeling in SHR,there are significant change of substance and energy metabolism.Ang II may be an important factor,which might influence the expression of BCKDK mediating catabolism of BCAA.Thus,BCAA regulate m TORC1 activity in hypertrophy of cells,fiber hyperplasia,mitochondrial structure and function and autophagy level,contributing to the progression of left ventricular remodeling of SHR.