Targeting oxidative stress-MMP-2 signaling in hypertension-induced cardiovascular remodeling and dysfunction

Excessive reactive oxygen and nitrogen species contribute to maladaptive structural and functional changes in the cardiovascular system in hypertension, including extracellular matrix proteolysis, vascular smooth muscle cell proliferation and arterial stiffness. A strong link exists between oxidative stress and increased matrix metalloproteinases (MMP) activity in inflammatory cardiovascular diseases. In particular, MMP-2 plays a central role in proteolytic processes in the vasculature and heart, contributing to maladaptive remodeling and dysfunction in hypertension. Oxidative stress regulates MMP expression and activity through transcriptional, post-transcriptional and post-translational mechanisms, including pathways mediated by peroxynitrite (ONOO^-)-dependent S-glutathiolation. This review provides a comprehensive overview of experimental and clinical evidence supporting the effects of enzymatic and non-enzymatic antioxidants, including dietary compounds such as polyphenols, carotenoids and vitamins, as well as pharmacological agents such as doxycycline, NADPH oxidase inhibitors, nitrite and hydrogen sulfide donors. Overall, antioxidants attenuate oxidative stress, improve nitric oxide bioavailability, reduce MMP activity and may ameliorate cardiovascular remodeling and dysfunction in experimental hypertension, although more clinical trials need to be performed to better translate such benefit effects in humans. A better understanding of antioxidant-mediated modulation of MMPs may support the development of novel therapeutic strategies to prevent or reduce hypertensive cardiovascular diseases.