An unexpected interaction between diabetes and cardiovascular diseases on cognitive function: A cross-sectional study.

OBJECTIVE: Impaired cognitive function in older individuals significantly affects quality of life. The interaction between comorbid diabetes and cardiovascular disease (CVD) and its impact on cognitive impairment remains unclear. METHODS: This study analyzed 2564 subjects from the National Health and Nutrition Examination Survey dataset. Cognitive function was measured using various scores, including CERAD Total Score, CERAD Delayed Recall Score (CDRS), Animal Fluency Total Score, and Digit Symbol Score. Multiple regression models were constructed to explore the relationship between different diseases and cognitive function, considering covariates such as age, sex, education, body mass index, alcohol intake, smoking, physical activity, kidney function, and hypertension. RESULTS: After adjusting for multiple factors, the presence of CVD, diabetes, or both showed a significant negative association with the total cognitive score. The CDRS was associated with both CVD and diabetes. The Digit Symbol score was associated with the presence of CVD, diabetes, or both. No significant differences were found between patients with diabetes and CVD in cognitive test results. An interaction between CVD and diabetes was observed in relation to the CDRS but not in other test scores or the total score. CONCLUSION: The individual impact of each disease on cognitive function was not significant. However, an interaction between CVD and diabetes was found when both diseases coexisted, specifically in relation to delayed learning ability.

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation.

Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

Ergosterol Attenuates Isoproterenol-Induced Myocardial Cardiotoxicity.

Phytomedicine has shown a promising potential for the prevention of cardiovascular system diseases and disorders. This study aimed to evaluate protective effect of ergosterol (ER) on isoproterenol (ISO)-induced myocardial cardiotoxicity. We found that pretreatment with ER significantly decreased levels of myocardial CK-MB and LDH, and alleviated myocardial damage induced by ISO in rat model. In addition, ER restored Nrf2 and HO-1 expression and inhibited apoptosis through upregulating Bcl-2 and downregulating Bax, cytochrome c, cleaved caspase-3, caspase-9, and PARP in rat hearts. Hypoxia-reoxygenation model in H9C2 cells confirmed the cardioprotective effects of ER. In conclusion, we provide both in vitro and in vivo evidence that ER significantly enhances Nrf2-mediated anti-oxidative activities, and exerts a protective effect on cardiomyocyte apoptosis. ER could be considered as a potential therapeutic agent to prevent myocardial injury.

The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-κB dependent downregulation of miRNA-143.

Untreated pathological cardiac hypertrophy, which can be caused by sustained systemic hypertension, may lead to heart failure. In the present study, we investigated whether AS-1 had attenuating effects on hypertension-induced cardiac hypertrophy, and whether this process was mediated by the regulation of miRNA-143. To induce the hypertrophic response in vitro, cardiomyocytes were stimulated with Ang II for 24hs. AS-1 administration strongly attenuated Ang II-induced hypertrophic response of cardiomyocytes. Chronical infusion of Ang II via implanted osmotic mini-pump induced increased blood pressure and cardiac hypertrophy in vivo. AS-1 administration attenuated hypertension-induced cardiac hypertrophy by, at least in part, inhibin of MAPK signaling. We observed, for the first time, upregulated expression of miRNA-143 in Ang II-induced cardiomyocytes, and inhibition of miRNA-143 significantly reduced the Ang II-induced hypertrophic responses. Importantly, AS-1 administration diminished the Ang II-induced upregulation of miRNA-143. Overexpression of miRNA-143 abolished the attenuating effects of AS-1 on Ang II-induced hypertrophic response of cardiomyocytes. Additionally, AS-1 administration abrogates Ang II-induced nuclear translocation of p50 NF-κB subunit in hypertrophic cardiomyocytes. Application of NF-κB inhibitor significantly suppressed Ang II-induced upregulation of miRNA-143. Our data suggest a novel mechanism by which AS-1 attenuates Ang II-induced hypertrophic response through downregulation miRNA-143 expression in a NF-κB-dependent manner.