A team of researchers affiliated with several institutions in Germany and one in Canada has found that it is possible to reprogram heart muscle to repair damaged tissue. In their paper published in the journal Science, the group describes their approach to repairing damaged hearts in mice and how well it worked when tested.
There are two main kinds of heart attack.
The first occurs when something prevents the heart from beating.
The second occurs when blood flow is restricted to parts of the heart, preventing the muscle in that area from beating.
The first kind is generally fatal unless the heart can be restarted very quickly. The second is generally less serious, but can leave permanent, debilitating scarring. In this new effort, the researchers have found a way to prevent such scarring – at least in mice.
The work built on prior research that showed that in the case of a baby experiencing heart damage in utero, the heart can repair itself because the cardiomyocyte cells are in a state that allows rejuvenation.
Their research showed that such factors express for cell renewal. The reprogramming also featured an on/off switch using the antibiotic doxycycline.
The researchers then tested their approach by giving mice with reprogrammed cells doxycycline just prior to and after inducing heart damage. They found that under both scenarios, heart regeneration occurred along with heart function improvement.
The researchers also tried giving similar test mice doxycycline six days after experiencing heart damage and found it had no impact. Thus, the window of repair is short. Further testing also showed that if doxycycline was administered for too long a period, cancerous tumors developed.
Segmental shortening in the border zone region adjacent to a myocardial infarction (MI) is depressed, even when the border zone has a normal blood supply [1]. While the decrease in border zone function was previously thought to be secondary to mechanical load [2], computational (finite element) modeling studies show that border zone contractility must be decreased by approximately 50% [3].
This finding has now been confirmed by studies in demembranated strips of myocardium obtained from the border zone after antero-apical MI in sheep [4].
The border zone in the current study is not the millimeter wide border zone comprised of interdigitating ischemic and normal myocardium described in the 1980s by Janse and others [5]. Rather, the border zone in the current study is a region with decreased contraction that is adjacent to the MI zone.
It is larger than previously thought, extending as far as 3 cm from the edge of the infarct [6] and the region of dysfunction expands in size over time [1]. Progression of border zone size and dysfunction may contribute to post-MI ventricular remodeling and subsequent heart failure [1].
Matrix metalloproteinases (MMP) were initially defined by their involvement in remodeling of the extracellular matrix. However, a specific MMP, matrix metalloproteinase-2 (MMP-2) also acts within the cardiomyocyte. Two discrete isoforms of intracellular MMP-2 have been identified. The first consists of the full length MMP-2 (FL-MMP-2) isoform previously considered to only have a role in cardiac extracellular matrix remodeling.
Several studies have shown that a significant fraction of synthesized FL-MMP-2 is retained in an enzymatically latent form within cardiomyocytes in direct association with sarcomeric components. Oxidative stress induced by ischemia/reperfusion injury can activate sarcomere-associated FL-MMP-2, an event that results in the cleavage of troponin I (TnI) [7], myosin light chain 1 (MLC-1) [8] and titin [9] with an associated reduction in contractile force.
In addition, a second recently characterized isoform of MMP-2 is generated by oxidative stress-mediated activation of an alternate promoter located in the first intron of the MMP-2 gene.
This event results in the synthesis of a N-terminal truncated isoform of MMP-2 (NTT-MMP-2) that remains intracellular, is enzymatically active, and is physically associated with mitochondria [10]. Cardiac-specific transgenic expression of the NTT-MMP-2 isoform results in inflammation, cardiomyocyte necrosis and impaired contractility due to defects in calcium handling [11, 12].
Studies of MMP inhibitors on LV function and remodeling after MI in animals and humans have had mixed results. Doxycycline increases wall thickness in the MI border zone and decreases passive compliance after coronary artery occlusion MI in the rat [13]. Relatively selective inhibition of MMPs 2, 3 and 13 (PD166793) decreases infarct expansion after coronary artery occlusion MI in the pig [14].
Short-term doxycycline therapy reduced LV remodeling in patients with acute ST-elevation myocardial infarction (TIPTOP trial) [15]. In contrast, non-selective inhibition of MMPs 2, 3, 8, 9, 13 and 14 (PG116800) had no beneficial effect on post-infarction LV remodeling in humans (PREMIER trial) [16]. To date, no studies have looked at the effect of MMP inhibition on post-myocardial ventricular function in the normally perfused LV border zone.
Doxycycline (Dox) non-selectively inhibits MMPs by chelating the structural Zn2+ required for catalytic activity [17]. In addition, doxycycline can inhibit MMP transcription. Doxycycline also has free radical scavenger, anti-apoptotic [17] and immune modulatory effects [18].
We recently reported that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone two weeks after infarction [4]. The purpose of the current study was therefore to determine if there is a sustained effect of short term treatment with doxycycline on border zone function in a large animal model of antero-apical MI.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809072/
More information: Yanpu Chen et al, Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice, Science (2021). DOI: 10.1126/science.abg5159
