Abstract Body (Do not enter title and authors here): Abstract
BACKGROUND: Heart failure remains a leading cause of morbidity and mortality worldwide,
yet despite advances in its management, the endogenous mechanisms that preserve
cardiomyocyte homeostasis under pathological stress are incompletely understood. Here, we
identify insulin-like growth factor binding protein 3 (IGFBP3) as a critical regulator of cardiac
proteostasis.
METHODS: To define the functional and mechanistic roles of IGFBP3 in cardioprotection, we
generated a novel tamoxifen-inducible, cardiomyocyte-specific IGFBP3 knockout mouse model
that was subjected to doxorubicin-induced cardiac injury, with cardiac function assessed by
serial echocardiography. To explore the clinical relevance of these findings, human data from
the UK Biobank were analyzed, where associations between circulating IGFBP3 levels, rare
deleterious IGFBP3 genetic variants, and incident heart failure and all-cause mortality were
examined.
RESULTS: IGFBP3 knockout mice exhibited accelerated systolic dysfunction, and increased
myocardial stiffness with associated persistent diastolic dysfunction following doxorubicin injury
compared to controls. Mechanistically, IGFBP3 deficiency in cardiomyocytes result in
pathological accumulation of misfolded sarcomeric proteins and detyrosinated microtubules,
thereby exacerbating proteotoxic stress. Translating these findings to humans, analysis of UK
Biobank data from 54,219 individuals revealed that lower circulating IGFBP3 levels are
independently associated with an increased risk of incident heart failure and all-cause mortality.
Moreover, genetic analysis of 454,787 participants revealed that carriers of rare,
deleterious IGFBP3 variants exhibit a significantly increased risk of heart failure and the
composite outcome of heart failure or death.
CONCLUSIONS: Our integrated findings establish IGFBP3 as an essential endogenous
regulator of cardiac proteostasis. IGFBP3 deficiency is critically implicated in adverse cardiac
outcomes, driving accelerated cardiac dysfunction in our knockout mouse model, and
associating with increased heart failure risk in humans. This study highlights the fundamental
role of IGFBP3 in preserving cardiomyocyte health under stress and injury conditions.