VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Abstract

Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands

“…This result is not inconsistent with recent work by the Alitalo group showing that therapeutic over-expression of VEGFB (which like PlGF binds only VEGFR1) in mice improves metabolic health even following endothelial Flt1 gene deletion, and inhibits doxorubicin-induced cardiotoxicity [54, 87]. Competition between ligands is concentration-dependent, and in these studies, VEGFB protein levels were elevated 20-fold or more in serum, heart, liver, and white adipose tissue.…”

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

“…Our data are in accordance with a previous study demonstrating that VO-PTEN inhibition promoted cell survival and decreased apoptosis postmyocardial infarction (16). Recently, a study by Rasanen et al (33) showed that VEGF-B inhibits DIC and prevents apoptotic cell death in endothelial cells; therefore, it would be interesting to analyze whether the PTEN inhibitor VO also inhibits endothelial cell apoptosis, in addition to the VSMCs and cardiomyocytes in the present study. Moreover, our data suggest that inhibition of PTEN by VO promotes myocardial cell survival after Doxo cardiotoxic assault through upregulation of the AKT pathway, which has been demonstrated in other adverse cardiac conditions (20,37).…”

Sulforaphane protection against the development of doxorubicin‐induced chronic heart failure is associated with Nrf2 Upregulation

“…The cumulative cardiotoxicity induced by DOX is associated with the development of chronic systolic and irreversible heart failure, which is related to the dosage and duration of treatment . Thus, the prevention of cardiac atrophy and dysfunction could improve the efficacy of cancer chemotherapy and enhance the chances of patient survival . Standard heart failure treatment should generally be initiated with the earliest detection of cardiotoxicity by a combination of biomarkers and imaging studies .…”