Each heartbeat results from a subtle balance between mechanical adaptation and cell regulation. When this balance breaks, the muscle transforms and thickens, setting up a defense response which can ultimately become deleterious. Cardiac hypertrophy is no longer a simple adjustment, but the first link in a pathological chain that research strives to understand and brake.
Among the first tips of tilting, researchers identify an abnormal accumulation of fibrous tissue and persistent inflammation. These phenomena gradually weaken the contractile capacity of the heart. They are often accompanied by a disorganization of cellular metabolism, an alteration of mitochondria and a runaway of cell death. All of these drifts constitute the foundations of pathological cardiac hypertrophy, a state that can evolve towards severe heart failure, sometimes irreversible.
In the case of patients with aortic stenosis, this hypertrophy settles slowly. Studies conducted on human biopsies have shown that the more the rate of fibrosis increases, the more the contractility of the muscle decreases. An observation which confirms the deleterious impact of tissue remodeling on heart performance, as highlighted by the team of Professor Manuel Vázquez-Carrera at the University of Barcelona, in the review Cellular and Molecular Life Sciences.
Gadd45a, a natural barrier against cardiac hypertrophy
At the heart of this complex mechanism, a protein hitherto little studied in the heart context plays an unexpected protective role. Called Gadd45a, this molecule normally intervenes in the regulation of cellular stress and DNA repair. But according to recent work carried out on genetically modified mice, it would also act as a regulator of the inflammatory and fibrotic response of the heart.
In animals deprived of this protein, researchers observed a marked deterioration of the heart structure. The muscle had extensive areas of fibrosis, infiltration of inflammatory cells and increased activity of the signaling pathways involved in hypertrophy, such as NF-κB, AP-1 and Stat3. Conversely, when researchers artificially increased the rate of gadd45a in human cardiac cells in culture, they found a clear decrease in pro-inflammatory signals triggered by TNF-α.
These results suggest that Gadd45a plays a natural brake role against the runoff of cardiac remodeling. By limiting the expression of certain pro-fibrotizing genes such as TGFB1 or COL1A1, it protects tissues against excessive rigidification. This mechanism could explain why certain hearts resist better than others with chronic overload, despite identical risk factors.
The study relayed in Scitechdaily also underlines that this protective function of Gadd45a is not limited to the heart. The protein seems to be involved in the prevention of inflammation and oxidation in several organs, and could more broadly influence the metabolic balance of the organism.
Why this discovery changes the situation for diabetic patients
Among the patients who are most exposed to cardiac hypertrophy, those with type 2 diabetes occupy a special place. Their hearts have to face a triple threat. A mechanical overload due to frequent hypertension, damage to vessels linked to atherosclerosis and a chronic metabolic imbalance. This combination promotes the emergence of aggressive cardiac remodeling, more difficult to reverse.
Researchers at the University of Barcelona also observed that the abolition of Gadd45a led to a fall in certain key genes of heart energy metabolism, such as PPARα or PDK4. This alteration reduces the capacity of the muscle to effectively use fatty acids and glucose, which could worsen heart vulnerability in insulin resistance contexts.
In parallel, mice devoid of Gadd45A had a pronounced hypertrophy of cardiac cells, associated with an imbalance between the AKT and AMPK tracks, two major regulators of cell growth and energy adaptation. This imbalance, often observed in diabetic patients, seems accentuated in the absence of gadd45a.
By highlighting this protein as a point of convergence between inflammation, metabolism and hypertrophy, the researchers then offer a promising target for future treatments. Restoring or stimulating gadd45a activity could make it possible to slow the progression of serious forms of hypertrophy cardiac, especially in patients whose metabolism is already weakened by diabetes.
