Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

Abstract

Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II–induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II–induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload–induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.

Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin II‐mediated BMP4‐oxidative stress cascade

“…The harmful effects of Ang II were inhibited by treatment with the AT1 receptor blocker losartan or the BMP4 antagonist noggin, suggesting that the improved endothelial function in db/db mice is probably attributable to boldine-induced inhibition of the Ang II-mediated BMP4 and associated oxidative stress in the vascular wall. A recent study also indicates a pathophysiological role of BMP4 in Ang II-induced cardiomycyte hypertrophy as Ang II stimulates BMP4 expression in cultured cardiac fibroblasts (Sun et al, 2013). However, the present study cannot discount the possible involvement of other BMP isoforms such as BMP2, BMP6 and BMP7 in oxidative stress and vascular inflammation in diabetic mice, which deserves future investigation.…”

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…This maneuvers increased systolic pressure around 1.5‐folds and induced cardiac hypertrophy. The chest was sutured and animals were kept until recovery of autonomic breath 24. After 4 weeks, LV tissue was separated and weighted and LV tissue was then rapidly frozen in liquid nitrogen and stored at −80°C for subsequent experiments.…”

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity

“…This mechanism may represent a failed attempt to downregulate plaque immune responses but may also undermine host-beneficial immunity, such as tissue healing (53). BMPs are best known as regulators of bone and cartilage formation (54), but BMP4 has been implicated in modifying disease mechanisms in several cardiovascular conditions, including atherosclerosis, hypertension, valvar abnormalities, pulmonary arterial hypertension, and myocardial ischemic injuries (55)(56)(57)(58)(59)(60). BMP4 is upregulated in atherosclerotic blood vessels, contributes to vascular calcification, and has been implicated in the progression of the atherosclerotic lesion (61).…”