PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, due to increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.

Restored autophagy is protective against PAK3-induced cardiac dysfunction.

Despite the development of clinical treatments, heart failure remains the leading cause of mortality. We observed that p21-activated kinase 3 (PAK3) was augmented in failing human and mouse hearts. Furthermore, mice with cardiac-specific PAK3 overexpression exhibited exacerbated pathological remodeling and deteriorated cardiac function. Myocardium with PAK3 overexpression displayed hypertrophic growth, excessive fibrosis, and aggravated apoptosis following isoprenaline stimulation as early as two days. Mechanistically, using cultured cardiomyocytes and human-relevant samples under distinct stimulations, we, for the first time, demonstrated that PAK3 acts as a suppressor of autophagy through hyper-activation of the mechanistic target of rapamycin complex 1 (mTORC1). Defective autophagy in the myocardium contributes to the progression of heart failure. More importantly, PAK3-provoked cardiac dysfunction was mitigated by administering an autophagic inducer. Our study illustrates a unique role of PAK3 in autophagy regulation and the therapeutic potential of targeting this axis for heart failure.

The multifaceted roles of ER and Golgi in metabolic cardiomyopathy.

Metabolic cardiomyopathy is a significant global financial and health challenge; however, pathophysiological mechanisms governing this entity remain poorly understood. Among the main features of metabolic cardiomyopathy, the changes to cellular lipid metabolism have been studied and targeted for the discovery of novel treatment strategies obtaining contrasting results. The endoplasmic reticulum (ER) and Golgi apparatus (GA) carry out protein modification, sorting, and secretion activities that are more commonly studied from the perspective of protein quality control; however, they also drive the maintenance of lipid homeostasis. In response to metabolic stress, ER and GA regulate the expression of genes involved in cardiac lipid biogenesis and participate in lipid droplet formation and degradation. Due to the varied roles these organelles play, this review will focus on recapitulating the alterations and crosstalk between ER, GA, and lipid metabolism in cardiac metabolic syndrome.

Multi-organ FGF21-FGFR1 signaling in metabolic health and disease.

Metabolic syndrome is a chronic systemic disease that is particularly manifested by obesity, diabetes, and hypertension, affecting multiple organs. The increasing prevalence of metabolic syndrome poses a threat to public health due to its complications, such as liver dysfunction and cardiovascular disease. Impaired adipose tissue plasticity is another factor contributing to metabolic syndrome. Emerging evidence demonstrates that fibroblast growth factors (FGFs) are critical players in organ crosstalk via binding to specific FGF receptors (FGFRs) and their co-receptors. FGFRs activation modulates intracellular responses in various cell types under metabolic stress. FGF21, in particular is considered as the key regulator for mediating systemic metabolic effects by binding to receptors FGFR1, FGFR3, and FGFR4. The complex of FGFR1 and beta Klotho (ß-KL) facilitates endocrine and paracrine communication networks that physiologically regulate global metabolism. This review will discuss FGF21-mediated FGFR1/ß-KL signaling pathways in the liver, adipose, and cardiovascular systems, as well as how this signaling is involved in the interplay of these organs during the metabolic syndrome. Furthermore, the clinical implications and therapeutic strategies for preventing metabolic syndrome and its complications by targeting FGFR1/ß-KL are also discussed.