Inhibition of a novel Dickkopf-1-LDL receptor-related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice.

BACKGROUND AND AIMS: Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. METHODS: The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. RESULTS: Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as ß-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. CONCLUSIONS: These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries.

Resveratrol prevents Ang II-induced cardiac hypertrophy by inhibition of NF-κB signaling.

BACKGROUND: Pathological cardiac hypertrophy is a hallmark of various cardiovascular diseases (CVD) including chronic heart failure (HF) and an important target for the treatment of these diseases. Aberrant activation of Angiotensin II (Ang II)/AT1R signaling pathway is one of the main triggers of cardiac hypertrophy, which further gives rise to excessive inflammation that is mediated by the key transcription factor NF-κB. Resveratrol (REV) is a natural polyphenol with multiple anti-inflammatory and anti-oxidative effects, however the ability of REV in preventing Ang II-induced cardiac hypertrophy in combination with NF-κB signaling activation remains unclear. METHODS: Murine models of cardiac hypertrophy was conducted via implantation of Ang II osmotic pumps. Primary neonatal rat cardiomyocyte and heart tissues were examined to determine the effect and underlying mechanism of REV in preventing Ang II-induced cardiac hypertrophy. RESULTS: Administrations of REV significantly prevented Ang II-induced cardiac hypertrophy, as well as robustly attenuated Ang II-induced cardiac fibrosis, and cardiac dysfunction. Furthermore, REV not only directly prevented Ang II/AT1R signal transductions, but also prevented Ang II-induced expressions of pro-inflammatory cytokines and activation of NF-κB signaling pathway. CONCLUSIONS: Our study provides important new mechanistic insight into the cardioprotective effects of REV in preventing Ang II-induced cardiac hypertrophy via inhibiting adverse NF-κB signaling activation. Our findings further suggest the therapeutic potential of REV as a promising drug for the treatment of cardiac hypertrophy and heart failure.

Liensinine prevents ischemic injury following myocardial infarction via inhibition of Wnt/ß­catenin signaling activation.

BACKGROUND: Myocardial infarction (MI) is the leading cause of deaths worldwide, triggering widespread and irreversible damage to the heart. Currently, there are no drugs that can reverse ischemic damage to the myocardium and hence, finding novel therapeutic agents that can limit the extent of myocardial damage following MI is crucial. Liensinine (LSN) is a naturally derived bisbenzylisoquinoline alkaloid that is known to exhibit numerous antioxidative and cardiovascular beneficial effects. However, the role of LSN in MI-induced injury and its underlying mechanisms remain unexplored. PURPOSE: Our study aims to evaluate the cardioprotective effects of LSN following MI and its underlying molecular mechanisms. METHODS: We constructed murine models of MI in order to examine the potential cardioprotective effects and mechanisms of LSN in protecting against myocardial ischemic damage both in vivo and in vitro. RESULTS: Administration with LSN strongly protected against cardiac injuries following MI by decreasing the extent of ischemic damage and improving cardiac function. Additionally, LSN was found to be a potent inhibitor of Wnt/ß­catenin signaling pathway. Hence, the beneficial effects of LSN in preventing oxidative and DNA damage following ischemia was due to its ability to inhibit aberrant activation of Wnt/ß­catenin signaling. CONCLUSIONS: Our findings reveal for the first time a novel cardioprotective role of LSN during myocardial infarction and most notably, its ability to protect cardiomyocytes against oxidative stress-induced damage via inhibiting Wnt/ß-catenin signaling. Our study therefore suggests new therapeutic potential of LSN or plants that contain the natural alkaloid LSN in ischemic heart diseases.