Calcification of myocardial necrosis is common in mice

Abstract

Independent of the severity, phenotypes and clinical outcomes of myocardial infarction may vary considerably in patients, suggesting a strong genetic influence on healing and adaptive processes. Since little is known about these genetic determinants, we examined the tissue response to myocardial injury in seven inbred mouse strains, including those employed for gene targeting or transgenic overexpression. Myocardial necrosis was produced by non-ischemic, trans-diaphragmal freeze-thaw injury in strains C57BL/6, C3H/He, DBA/2, BALB/c, 129S1, FVB/n and A/J. Two days after injury, necrotic cardiomyocytes calcified in C3H/He, DBA/2, BALB/c and 129S1, a phenotype known as dystrophic cardiac calcinosis (DCC). The susceptibility to DCC of 129S1 was determined by Dyscalc1, a locus on chromosome 7, which was identified previously in C3H/He and DBA/2. DCC was also observed in C3H/He following ischemic injury by permanent coronary artery ligation, indicating that DCC was independent of the mode of injury. In contrast, strains C57BL/6, FVB and A/J were resistant to DCC, showing formation of a fibrous scar without calcification. The development of DCC was studied in detail in C3H/He and C57BL/6. In both strains, no calcium deposition and only little structural disintegration were noted in necrotic myocardium 24 h after injury upon calcium-sensitive fluorescence staining. Ultrastructural examination revealed calcified mitochondria in C3H/He that may have served later as a nidus for rapid intracellular calcification of cardiomyocytes. We concluded that the susceptibility to calcification of myocardial necrosis may be common among inbred strains and should be recognised as a strong genetic modifier of experimental myocardial injury.

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification

“…Cardiac injury or aging in certain strains of mice (e.g. C3H/HeJ, BALB/cByJ, DBA/2J) can lead to the development of calcification within the myocardium (Glass et al, 2013);(Ivandic et al, 1996);(Korff et al, 2006). We used several different methods to induce myocardial injury in C3H strain of mice.…”

“…Cryo-probe mediated injury of the mid ventricle (Aherrahrou et al, 2004) also resulted in calcification of the injury region within 7 days of injury (Figure 2E,F). Finally, ischemic injury of the myocardium by ligating the left anterior descending (LAD) coronary artery, (Korff et al, 2006) led to patchy calcification of the injury region within 4 weeks of ischemic insult (Figure 2G,H). Consistent with the known association of fibrosis and calcification, we observed calcification only in regions where there was fibrosis (identified by Masson trichrome staining) (Figure 2 I , J).…”

“…For cryo-injury, mice were deeply anesthetized with 2% isoflurane, maintained at 1.5–2% isoflurane, and intubated using a volume-cycled ventilator. A left thoracotomy was performed at the level of 2nd intercostal space and the exposed beating heart was frozen for 10 seconds by gently pressing a pre-cooled steel rod of 1mm diameter in dry ice (Aherrahrou et al, 2004);(Korff et al, 2006). Freezing of cardiac tissue was confirmed by the rapid discoloration of the tissue.…”

Myocardial calcification and subendocardial fatty replacement of the left ventricle following myocardial infarction

“…The subsequent response of tissue involves inflammation and removal of necrotic tissue and usually results in scarring and thinning of the affected myocardial wall. Interestingly, up to 7.6% of the survivors of acute myocardial infarctions may also exhibit calcified myocardial necrosis [2].…”

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome

“…Mitochondria are calcium rich; sufficiently calcium rich that mitochondrial disruption and release of calcium can produce dystrophic calcification, as observed in necrotic myocardium 41 . Conversely, cardiac mitochondria can act as calcium sponges, taking up and buffering available free cytosolic calcium 42 .…”