Lactate metabolism and lactylation in cardiovascular disease: novel mechanisms and therapeutic targets

Cardiovascular disease (CVD) is responsible for approximately 30% of annual global mortality rates, yet existing treatments for this condition are considered less than ideal. Despite being previously overlooked, lactate, a byproduct of glycolysis, is now acknowledged for its crucial role in the cellular functions of the cardiovascular system. Recent studies have shown that lactate influences the proliferation, differentiation, and activation of immune cells through its modulation of post-translational protein modifications, thereby affecting the development and prognosis of cardiovascular disease. Consequently, there has been a notable increase in interest towards drug targets targeting lactylation in immune cells, prompting further exploration. In light of the swift advancements in this domain, this review article is dedicated to examining lactylation in cardiovascular disease and potential drug targets for regulating lactylation, with the aim of enhancing comprehension of this intricate field

KLF1 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through Regulation of Wnt/β‐Catenin Signaling Pathway

Abstract Innovative therapeutic approaches for heart failure, a leading cause of mortality worldwide, are urgently needed. In this study, the important role of Krüppel‐like factor 1 (KLF1) in cardiomyocyte proliferation and heart regeneration is explored, and revealed its ability to regulate the Wnt/β‐catenin signaling pathway as well as exploring a feasible strategy to target KLF1 for the treatment of heart failure. Postnatally, a marked decrease in KLF1 expression occurred almost simultaneously with a reduction in myocardial regenerative capacity. Through comprehensive in vivo and in vitro studies, it is demonstrated that in neonatal and adult mice, KLF1 overexpression significantly increased cardiomyocyte proliferation and promoted myocardial repair following infarction, whereas KLF1 knockout abolished these effects. Mechanistically, through RNA sequencing (RNA‐seq) and ATAC sequencing (ATAC‐seq) analyses, it is revealed that the promotion of cardiomyocyte proliferation by KLF1 is associated with the Wnt/β‐catenin signaling pathway, mitochondrial function, and fatty acid metabolism. These findings highlight the important role of KLF1 in cardiomyocyte proliferation and heart regeneration, which provides novel insights into therapeutic targets for heart failure

Effects and mechanisms of the myocardial microenvironment on cardiomyocyte proliferation and regeneration

The adult mammalian cardiomyocyte has a limited capacity for self-renewal, which leads to the irreversible heart dysfunction and poses a significant threat to myocardial infarction patients. In the past decades, research efforts have been predominantly concentrated on the cardiomyocyte proliferation and heart regeneration. However, the heart is a complex organ that comprises not only cardiomyocytes but also numerous noncardiomyocyte cells, all playing integral roles in maintaining cardiac function. In addition, cardiomyocytes are exposed to a dynamically changing physical environment that includes oxygen saturation and mechanical forces. Recently, a growing number of studies on myocardial microenvironment in cardiomyocyte proliferation and heart regeneration is ongoing. In this review, we provide an overview of recent advances in myocardial microenvironment, which plays an important role in cardiomyocyte proliferation and heart regeneration