Murine ventricular cardiomyocytes (CM) are still immature at birth. Within 1 month after the birth, they are maturated through physiological hypertrophy, enrichment of sarcoplasmic reticulum and formation of t-tubules bearing abundant L-type Ca2+ channels. This channel is involved in Ca2+-induced Ca2+ release that causes maturated excitation-contraction and forceful ventricular contraction. In heart, the concentration of several cytokines, growth factors and hormones are known to change after birth. However, it is unclear which of the factors are responsible for the final CM maturation in mice.
The effects of various inhibitors of receptors for these factors on final CM maturation were assessed in P1-20 mice. Their cardiac function was evaluated with echocardiogram. Morphology of t-tubules and a twitch Ca2+ transient were analyzed in the isolated CM.
Cardiac function was significantly lower in mice treated with nintedanib, an inhibitor of FGF, PDGF and VEGF receptors, or SC-144, gp130 antagonist than control mice. The nintedanib-treated mice also exhibited smaller peak of Ca2+ transients. We are intending to determine which of the factors are necessary for the CM maturation by using shRNA delivered with adeno-associated virus in living mice.