MMP inhibitor(Paratek Pharmaceuticals)

Cardiovascular disorders (CVDs) remain the leading cause of global mortality, surpassing other chronic illnesses. An alarming rise in CVD-related deaths, particularly among younger populations, has intensified research efforts to better understand the disease and its complications. Among these, myocardial fibrosis plays a central role in the development of cardiac dysfunction and heart failure. Given its multifactorial nature, diverse therapeutic strategies are required to manage its progression effectively.

A comprehensive literature review was conducted using databases such as PubMed, Scopus, Elsevier, and ClinicalTrials.gov. Only peer-reviewed, English-language studies focusing on molecular mechanisms and therapeutic strategies for myocardial fibrosis were included. Irrelevant, non-English, and non-peer-reviewed sources were excluded. Data from selected preclinical and clinical investigations were qualitatively synthesized.

Myocardial fibrosis arises from various pathological conditions, including ischemia, hyperlipidemia, and genetic disorders, which promote maladaptive cardiac remodeling. Although traditional treatments such as RAAS inhibitors and β-blockers offer symptomatic relief, they do not halt disease progression. Recent evidence suggests that multiple molecular pathways are involved in the development of fibrosis, opening opportunities to explore alternative therapeutic targets.

Due to its complex pathophysiology, myocardial fibrosis cannot be addressed by monotherapy alone. Anti-TGF-β agents have emerged as promising candidates, alongside newer therapies like SGLT2 inhibitors and MMP inhibitors. Additionally, regenerative approaches, such as stem cell and gene therapy, offer future avenues, though technical and safety challenges accompany them.

Myocardial fibrosis remains a critical contributor to heart failure, and current treatments are insufficient to reverse its course. A multifaceted therapeutic approach targeting different molecular mechanisms holds the key to improved clinical outcomes. Continued translational research is crucial for advancing emerging therapies from bench to bedside.

Treatment of cancer patients with anthracyclines is known to cause dose‐dependent cardiotoxicity through several mechanisms including enhanced oxidative stress, ultimately resulting in defective excitation–contraction coupling. Loss of junctophilin‐2 (JPH‐2), which tethers transverse tubules (T‐tubules) to the sarcoplasmic reticulum, is a feature of doxorubicin‐induced cardiotoxicity, yet the protease involved in unclear. As activation of matrix metalloproteinase‐2 (MMP‐2) is known to contribute to doxorubicin‐induced cardiotoxicity, we investigated here the role of MMP‐2 in JPH‐2 proteolysis and defective calcium transients in it.

C57BL/6J mice were treated with doxorubicin for 4 weeks with or without the MMP inhibitor (doxycycline), MMP‐2 preferring inhibitor (ONO‐4817) or vehicle, and cardiac function was assessed using echocardiography. JPH‐2 levels in ventricular extracts were measured. Calcium transients and JPH‐2 levels were measured in neonatal rat ventricular cardiomyocytes treated with doxorubicin and ONO‐4817.

Both MMP inhibitors attenuated doxorubicin‐induced cardiac systolic and diastolic dysfunction. Doxorubicin treatment resulted in JPH‐2 cleavage in mouse hearts as evidenced by the appearance of lower molecular weight products of 63 and 25 kDa, which was prevented by MMP inhibitors. Loss of JPH‐2 and impaired calcium transients were observed in neonatal rat ventricular cardiomyocytes treated with doxorubicin, while ONO‐4817 attenuated these changes. In silico analysis predicted cleavage sites between JPH‐2 MORN repeats and within its unstructured region.

These results reveal that JPH‐2 proteolysis is a consequence of MMP‐2 activation and highlight the beneficial prophylactic action of two orally available MMP inhibitors in preventing doxorubicin‐induced cardiotoxicity.