Study explores new benefits of beta-blockers for heart health
UK: A recent study published in the journal Circulation has suggested a beneficial effect of beta-blockers on the heart proteoglycan content. Chondroitin sulphate proteoglycans (CSPGs), a group of proteins that accumulates in the heart of patients with heart failure (HF). ADAMTS5 cleaves CSPGs such as versican.
"Our results in patients and animal models show that ADAMTS proteases are important for the degradation of versican in the heart and the accumulation of versican is associated with impaired cardiac function," Javier Barallobre-Barreiro and the team wrote.
Beta-blockers are a group of drugs that slow down the heart rate. They work by blocking the action of stress hormones – adrenaline, noradrenaline – stopping them from binding to receptors on heart cells.
A hallmark of heart failure is the remodeling of the extracellular matrix (ECM). Previous analyses of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulphate proteoglycans (CSPGs). The contribution of ADAMTS5 and its substrate versican to HF is unknown.
To determine the above, Barallobre-Barreiro and the team assessed versican remodeling in mice lacking the catalytic domain of ADAMTS5 (Adamts5â–³Cat). Proteomics was applied to study ECM remodeling in left ventricular samples from HF patients, with a particular focus on the effects of common medications used for the treatment of HF.
Based on their study, the researchers found the following:
- Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in ischemic HF patients.
- Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II (Ang II) infusion.
- In Adamts5â–³Cat mice, Ang II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin beta 1, filamin A and connexin 43.
- Echocardiographic assessment of Adamts5â–³Cat mice revealed a reduced ejection fraction and an impaired global longitudinal strain upon Ang II infusion.
- Cardiac hypertrophy and collagen deposition, however, were similar to littermate controls.
- In a proteomics analysis of a larger cohort of cardiac explants from ischemic HF patients (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes.
- Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, HF patients treated with β-blockers had a distinct cardiac ECM profile.
"A comprehensive characterization of the cardiac ECM in ischemic HF patients revealed that β−blockers may have a previously unrecognized beneficial effect on the cardiac CSPG content," the researchers concluded.
Reference:
The study titled, "The Extracellular Matrix in Heart Failure: The Role of Adamts5 In Proteoglycan Remodelling," is published in the journal Circulation.
DOI: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.055732
