investigating-pathogenesis-myh7-mutation-gly823glu-familial

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Familial hypertrophic cardiomyopathy (HCM, OMIM: 613690) is the most common cardiomyopathy in China. However, the underlying genetic etiology of HCM ...

Guangdong Laboratory Animals Monitoring Institute

The secreted glycoprotein Slit2, previously known as an axon guidance cue, has recently been found to protect tissues in pathological conditions; however, it is unknown whether Slit2 functions in cardiac ischemia-reperfusion (IR) injury.

Slit2 Protects Hearts Against Ischemia-Reperfusion Injury by Inhibiting Inflammatory Responses and Maintaining Myofilament Contractile Properties.

Aged nonhuman primate (NHP) models are of great value for studying the pathology of metabolic heart diseases and developing therapeutic strategies. In this study, aged male cynomolgus monkeys were fed a regular diet or a high-fat/high-sugar diet (HFSD) for 8 months. Metabolic disorders were diagnosed by H-NMR and serum biochemistry, and cardiac function was evaluated by echocardiography. Our results showed that serum metabolic profiles were altered in aged monkeys fed a HFSD, in line with aortic tissue damage, cardiac remodeling, and contractile dysfunction. This aged monkey model significantly increased expression of proinflammatory cytokines and altered expression and phosphorylation of intracellular signaling proteins in the heart, as compared to aged monkeys on a regular diet. Furthermore, the animals demonstrated increased phosphorylation of cardiac myofilament proteins which are causatively associated with decreased myofilament contractility. We conclude that the aged monkey model fed a HFSD exhibits metabolic disorders and cardiac contractile dysfunction.

Aged Monkeys Fed a High-Fat/High-Sugar Diet Recapitulate Metabolic Disorders and Cardiac Contractile Dysfunction.

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at >50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling.

 Pressure overload can result in dilated cardiomyopathy. The beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) on heart disorders have been widely recognized. However, the molecular mechanisms underlying their protective effects against cardiomyopathy remain unclear.  Pressure overload in mice induced by 8 weeks of transverse aortic constriction was used to induce dilated cardiomyopathy. A transgenic fat-1 mouse model carrying the n-3 fatty acid desaturase gene fat-1 gene from  was used to evaluate the mechanism of n-3 PUFAs in this disease. Echocardiography, transmission electron microscopy, and histopathological analyses were used to evaluate the structural integrity and function in pressure overloaded fat-1 hearts. mRNA sequencing, label-free phosphoprotein quantification, lipidomics, Western blotting, RT-qPCR, and ATP detection were performed to examine the effects of n-3 PUFAs in the heart.  Compared with wild-type hearts, left ventricular ejection fraction was significantly improved (C57BL/6J [32%] vs. fat-1 [53%]), while the internal diameters of the left ventricle at systole and diastole were reduced in the fat-1 pressure overload hearts. mRNA expression, protein phosphorylation and lipid metabolism were remodeled by pressure overload in wild-type and fat-1 hearts. Specifically, elevation of endogenous n-3 PUFAs maintained the phosphorylation states of proteins in the subcellular compartments of sarcomeres, cytoplasm, membranes, sarcoplasmic reticulum, and mitochondria. Moreover, transcriptomic analysis predicted that endogenous n-3 PUFAs restored mitochondrial respiratory chain function that was lost in the dilated hearts, and this was supported by reductions in detrimental oxylipins and protection of mitochondrial structure, oxidative phosphorylation, and ATP production.  Endogenous n-3 PUFAs prevents dilated cardiomyopathy via orchestrating gene expression, protein phosphorylation, and lipid metabolism. This is the first study provides mechanistic insights into the cardioprotective effects of n-3 PUFAs in dilated cardiomyopathy through integrated multi-omics data analysis.

Cardioprotective Effects of n-3 Polyunsaturated Fatty Acids: Orchestration of mRNA Expression, Protein Phosphorylation, and Lipid Metabolism in Pressure Overload Hearts.

The murine transverse aortic constriction (TAC) model is frequently used to investigate molecular mechanisms underlying heart failure. However, limited data is available regarding the expression of mRNAs and circRNAs in murine heart failure progression induced by pressure overload.

Differential mRNA Expression and Circular RNA-Based Competitive Endogenous RNA Networks in the Three Stages of Heart Failure in Transverse Aortic Constriction Mice.

Article	Year
Slit2 Protects Hearts Against Ischemia-Reperfusion Injury by Inhibiting Inflammatory Responses and Maintaining Myofilament Contractile Properties. Frontiers in physiology\| PubMed ID: 32292352	2020
Aged Monkeys Fed a High-Fat/High-Sugar Diet Recapitulate Metabolic Disorders and Cardiac Contractile Dysfunction. Journal of cardiovascular translational research\| PubMed ID: 33591467	2021
A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling. Frontiers in cardiovascular medicine\| PubMed ID: 34150870	2021
Cardioprotective Effects of n-3 Polyunsaturated Fatty Acids: Orchestration of mRNA Expression, Protein Phosphorylation, and Lipid Metabolism in Pressure Overload Hearts. Frontiers in cardiovascular medicine\| PubMed ID: 35047577	2021
Differential mRNA Expression and Circular RNA-Based Competitive Endogenous RNA Networks in the Three Stages of Heart Failure in Transverse Aortic Constriction Mice. Frontiers in physiology\| PubMed ID: 35330931	2022

Shuang Zheng

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