Cardiovascular‐specific PSEN1 deletion leads to abnormalities in calcium homeostasis

Abstract

Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia‐induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a‐PSEN1‐KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a‐PSEN1‐KO group compared with the percent of these measures in the WT group, indicating that PSEN1‐KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1‐KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1‐KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging‐related cardiomyopathy, which might had important implications for the treatment of aging‐related heart diseases.

Abnormal expression of PRKAG2-AS results in dysfunction of cardiomyocytes through regulating PRKAG2 transcription by interacting with PPARG

“…ANP is secreted by cardiomyocytes and plays a crucial role in regulating natriuretic, vasodilator, and diuretic effects. BNP , released following acute myocardial infarction, can reflect the prognosis of patients during the acute phase [ 20 ]. Altered expression levels of these hormones are characteristic of cardiac insufficiency.…”

“…The collection of clinical specimens was approved by the Ethics Committee of the Second Military Medical University (approval code: NMU8217021385). As described before [ 20 , 21 ], all human heart samples used in this study were from patients who had organ transplants in ChangHai Hospital from 2012 to 2018 with informed consent from the patients or their families (approval code: SMMU913293039). ICM and DCM samples came from the abandoned hearts of heart transplant acceptors after surgery.…”

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

“…PSEN1 knockout mice with heart failure presented lower calcium levels in the SR when compared to the wild-type mice with heart failure. PSEN1 abnormalities may result in dysfunctions of the calcium balance in failing hearts, which might impact the onset of aging-related cardiomyopathy [79]. (See Figure 4).…”