Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin

Abstract

Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis

“…Protein concentrations were determined using a BCA Protein Assay Kit (Beyotime, P0010). Western blot was performed as described previously 32, 33. The primary antibodies used are presented in Table S8.…”

Genomic characterization reveals novel mechanisms underlying the valosin-containing protein-mediated cardiac protection against heart failure

“…However, it is unclear whether this deficiency of VCP found in the hypertensive hearts is only an accompanying consequence of the cardiac response caused by pressure overload or is a contributor that mediates the cardiac deteriorations. We selected 5 W TAC to test the effects of VCP on pressure overload-induced heart failure for the following reasons: first, this model is an established and the most common heart failure mouse model that has been widely used to mimic human pressure-overload induced cardiac remodeling and dysfunction [ [31] , [32] , [33] , [34] , [35] ]. Numerous studies have confirmed that TAC could provide a reproducible model of cardiac hypertrophy, inflammatory and fibrotic response, and a gradual time course in the development of heart failure [ [31] , [32] , [33] , [34] , 36 ].…”

“…We selected 5 W TAC to test the effects of VCP on pressure overload-induced heart failure for the following reasons: first, this model is an established and the most common heart failure mouse model that has been widely used to mimic human pressure-overload induced cardiac remodeling and dysfunction [ [31] , [32] , [33] , [34] , [35] ]. Numerous studies have confirmed that TAC could provide a reproducible model of cardiac hypertrophy, inflammatory and fibrotic response, and a gradual time course in the development of heart failure [ [31] , [32] , [33] , [34] , 36 ]. Secondly, TAC could mimic pressure-overload induced morphological and functional alterations of hypertension but excludes the impacts of other potential factors on the molecular alterations that may exist in other hypertensive models, such as the genetic and environmental effects and drug treatments.…”

EGCG inhibits pressure overload‐induced cardiac hypertrophy via the PSMB5/Nmnat2/SIRT6‐dependent signalling pathways

“…Cardiac hypertrophy, a morphological adaptive response of the heart to chronic work overload, is characterized by an increase in cardiomyocyte size, enhanced protein synthesis, and re‐expression of the foetal cardiac gene program. Although cardiac hypertrophy is initially a compensatory mechanism, chronic pathological hypertrophy may be deleterious, as it is associated with an increased risk of heart failure and premature death 1‐3 . Although much progress has been made to understand the molecular mechanism of cardiac hypertrophy over the past few decades, the pathogenesis of this disease is yet to be clarified.…”

“…Although cardiac hypertrophy is initially a compensatory mechanism, chronic pathological hypertrophy may be deleterious, as it is associated with an increased risk of heart failure and premature death. [1][2][3] Although much progress has been made to understand the molecular mechanism of cardiac hypertrophy over the past few decades, the pathogenesis of this disease is yet to be clarified.…”