Background—: Carnitine palmitoyltransferase-1 (CPT1) is a rate-limiting step of mitochondrial β-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT1 activity by specific CPT1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby creating concerns about the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 to evaluate it as a safe and effective therapeutic approach. Methods and Results—: Heterozygous CPT1b knockout (CPT1b ^+/− ) mice were subjected to transverse aorta constriction–induced pressure overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by 2 weeks of transverse aorta constriction, CPT1b ^+/− mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b ^+/− mice exhibited exacerbated cardiac hypertrophy and remodeling compared with wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b ^+/− mice than in control mice. Moreover, the CPT1b ^+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocyte apoptosis. Conclusions—: CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be exercised in the clinical use of CPT1 inhibitors.

Zebrafish can efficiently regenerate their heart through cardiomyocyte proliferation. In contrast, mammalian cardiomyocytes stop proliferating shortly after birth, limiting the regenerative capacity of the postnatal mammalian heart. Therefore, if the endogenous potential of postnatal cardiomyocyte proliferation could be enhanced, it could offer a promising future therapy for heart failure patients. Here, we set out to systematically identify small molecules triggering postnatal cardiomyocyte proliferation. By screening chemical compound libraries utilizing a Fucci-based system for assessing cell cycle stages, we identified carbacyclin as an inducer of postnatal cardiomyocyte proliferation. In vitro, carbacyclin induced proliferation of neonatal and adult mononuclear rat cardiomyocytes via a peroxisome proliferator-activated receptor δ (PPARδ)/PDK1/p308Akt/GSK3β/β-catenin pathway. Inhibition of PPARδ reduced cardiomyocyte proliferation during zebrafish heart regeneration. Notably, inducible cardiomyocyte-specific overexpression of constitutively active PPARδ as well as treatment with PPARδ agonist after myocardial infarction in mice induced cell cycle progression in cardiomyocytes, reduced scarring, and improved cardiac function. Collectively, we established a cardiomyocyte proliferation screening system and present a new drugable target with promise for the treatment of cardiac pathologies caused by cardiomyocyte loss.

Honokiol is a key component of a medicinal herb, Magnolia bark. Honokiol possesses potential pharmacological benefits for many disease conditions, especially cancer. Recent studies demonstrate that Honokiol exerts beneficial effects on cardiac hypertrophy and doxorubicin (Dox)-cardiotoxicity via deacetylation of mitochondrial proteins. However, the effects and mechanisms of Honokiol on cardiac mitochondrial respiration remain unclear. In the present study, we investigate the effect of Honokiol on cardiac mitochondrial respiration in mice subjected to Dox treatment. Oxygen consumption in freshly isolated mitochondria from mice treated with Honokiol showed enhanced mitochondrial respiration. The Dox-induced impairment of mitochondrial respiration was less pronounced in honokiol-treated than control mice. Furthermore, Luciferase reporter assay reveals that Honokiol modestly increased PPARγ transcriptional activities in cultured embryonic rat cardiomyocytes (H9c2). Honokiol upregulated the expression of PPARγ in the mouse heart. Honokiol repressed cardiac inflammatory responses and oxidative stress in mice subjected to Dox treatment. As a result, Honokiol alleviated Dox-cardiotoxicity with improved cardiac function and reduced cardiomyocyte apoptosis. We conclude that Honokiol protects the heart from Dox-cardiotoxicity via improving mitochondrial function by not only repressing mitochondrial protein acetylation but also enhancing PPARγ activity in the heart. This study further supports Honokiol as a promising therapy for cancer patients receiving Dox treatment.

Adiponectin, an adipocyte-derived hormone, is a versatile player involved in the regulation of energy homeostasis, cardiovascular disease, and diabetes. Within adipocytes, adiponectin is retained in the lumen of the endoplasmic reticulum (ER) by binding to the thiol protein ER resident protein 44 kDa (ERp44), which is apparently regulated by the activation of nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ. However, the precise role of ERp44 in adiponectin secretion remains elusive. In the present study, we investigated the functional correlation between ERp44 and adiponectin in a pig model. The transcription of porcine ERp44 was regulated by PPARγ, which was consistent with the finding of putative peroxisome proliferator response element sites within ERp44 promoter. Using chromatin immunoprecipitation and luciferase reporter assays, we demonstrated that the transcription of porcine ERp44 is repressed through binding of PPARγ to a peroxisome proliferator response element site located between positions −981 and −1004 in its 5′-flanking region. In human embryonic kidney 293 cells stably transfected with cDNA encoding porcine adiponectin, the secretion of adiponectin was significantly up-regulated and the ERp44 mRNA was down-regulated observably, by either the treatment of PPARγ agonist rosiglitazone or the overexpression of PPARγ in these cells. Taken together, our results indicated that PPARγ is an essential regulatory factor for the transcriptional activity of ERp44, which in turn controls the secretion of adiponectin.

Ganoderma lucidum is a Chinese medicinal fungus with a long history of use in healthcare and disease treatment. G. lucidum spores (GLS) are tiny germ cells released from the mushroom cap during the mature stage of growth. They contain all the genetic active substances of G. lucidum. G. lucidum spore oil (GLSO) is a lipid component extracted from broken-walled Ganoderma spores using supercritical CO₂ extraction technology. GLSO contains fatty acids, Ganoderma triterpenes, sterols and other bioactive compounds. Previous studies have demonstrated that GLSO has a wide range of pharmacological properties, including anti-tumor, anti-aging, neuroprotection, immunomodulation, hepatoprotection and modulation of metabolic diseases. This review summarizes the research progress of GLSO over the past two decades in terms of its bioactive components, extraction and processing techniques, pharmacological effects and safety evaluation. This provides a solid foundation for further research and application of GLSO.