Title:Cellular and Mitochondrial Pathways Contribute to SGLT2
Inhibitors-mediated Tissue Protection: Experimental and Clinical Data
Volume: 30
Issue: 13
Author(s): Raúl Lelio Sanz, Sebastián García Menéndez, Felipe Inserra, León Ferder and Walter Manucha*
Affiliation:
- Departamento de Patologie et Pharmacologie, Instituto de Medicina y Biologia Experimental de Cuyo, Consejo Nacional de Investigación Cientifica y Tecnológica (IMBECU- CONICET), Mendoza 5500, Argentina
- Laboratorio de Farmacologia Experimental Básica y Traslacional, Departamento de Patologie et Pharmacologie, Área de Farmacologia, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina
Keywords:
SGLT2i, cardiovascular diseases, sirtuins, oxidative stress, inflammation, mitochondrial dysfunction.
Abstract: In metabolic syndrome and diabetes, compromised mitochondrial function emerges as a critical driver
of cardiovascular disease, fueling its development and persistence, culminating in cardiac remodeling and
adverse events. In this context, angiotensin II - the main interlocutor of the renin-angiotensin-aldosterone system
- promotes local and systemic oxidative inflammatory processes. To highlight, the low activity/expression
of proteins called sirtuins negatively participates in these processes, allowing more significant oxidative imbalance,
which impacts cellular and tissue responses, causing tissue damage, inflammation, and cardiac and vascular
remodeling. The reduction in energy production of mitochondria has been widely described as a significant
element in all types of metabolic disorders. Additionally, high sirtuin levels and AMPK signaling stimulate hypoxia-
inducible factor 1 beta and promote ketonemia. Consequently, enhanced autophagy and mitophagy advance
through cardiac cells, sweeping away debris and silencing the orchestra of oxidative stress and inflammation,
ultimately protecting vulnerable tissue from damage. To highlight and of particular interest, SGLT2 inhibitors
(SGLT2i) profoundly influence all these mechanisms. Randomized clinical trials have evidenced a
compelling picture of SGLT2i emerging as game-changers, wielding their power to demonstrably improve cardiac
function and slash the rates of cardiovascular and renal events. Furthermore, driven by recent evidence,
SGLT2i emerge as cellular supermolecules, exerting their beneficial actions to increase mitochondrial efficiency,
alleviate oxidative stress, and curb severe inflammation. Its actions strengthen tissues and create a resilient
defense against disease. In conclusion, like a treasure chest brimming with untold riches, the influence of
SGLT2i on mitochondrial function holds untold potential for cardiovascular health. Unlocking these secrets,
like a map guiding adventurers to hidden riches, promises to pave the way for even more potent therapeutic
strategies.
