ROCK as a molecular bond connecting coronary microvascular and cardiac remodelling

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    Coronary microvascular resistance is modulated by a variety of factors including extravascular compressive forces and the regulation ofmicrovascular tone, which involves the interplay between metabolic, myogenic, neurohumoral, and endotheliumderived factors. Together these mechanisms modulate coronary blood flow and act to sustain an adequate balance between myocardial oxygen delivery (supply) and metabolism (demand).

     Pathological conditions such as coarctation of the aorta physiologically constrain the balance between coronary blood flow and myocardial metabolism by augmenting extravascular compressive forces and elevating left ventricular afterload. These changes not only result in immediate metabolic adjustments of coronary microvascular resistance but also induce neurohumoral activation which increases oxidative stress and promotes chronic impairment of coronary microvascular function. (Picture 1).

This microvascular dysfunction is generally characterized by a change in production of vasodilators [nitric oxide (NO), endothelium derived hyperpolarizing factor (EDHF), prostacyclin, hydrogen peroxide] relative to vasoconstrictors [endothelin (ET), thromboxane A2, superoxide]. Particularly NO and ET are well-known modulators of cardiovascular function. NO activates guanylyl cyclase leading to cyclic guanylyl monophosphate (cGMP) production, protein kinase G (PKG) activation, and relaxation of vascular smooth muscle cells. Conversely, ET is known to promote profound vasoconstriction and vascular remodelling via its binding to the ETA receptor and activation of RhoA/Rho-kinase (ROCK) signaling.

     The communication between cardiomyocytes and the coronary microvasculature not only involves signals from the myocytes to the vasculature, but factors released from the coronary endothelium also exert a paracrine effect on the surrounding cardiomyocytes. NO promotes cardiomyocyte relaxation and acts as a break on the ET-induced RhoA/ROCK mediated myocyte hypertrophy. Endothelial dysfunction can therefore contribute to development and/or progression of cardiac dysfunction not only through impaired oxygenation of the myocardium but also through altered paracrine modulation of cardiomyocyte function.

     The ROCK inhibitor fasudil has first been used to treat cerebral vasospasm, and, importantly, had no serious side effects.8 Clinical studies further support the potential for ROCK to alleviate symptoms of pulmonary hypertension9 and improve vasospastic coronary angina.

     Finally, ROCK inhibition has shown promising effects in preclinical studies in hypertension, atherosclerosis, and ischaemia reperfusion injury. That's why therapeutic targeting of ROCK may be particularly useful in the treatment of cardiac diastolic dysfunction associated with chronic volume and/or pressure overload in which perivascular fibrosis and microvascular dysfunction and cardiomyocyte dysfunction are linked.

Source of information: "ROCK as a molecular bond connecting coronary microvascular and cardiac remodelling", Daphne Merkus and Johnathan D Tune, Cardiovascular Research (2017) 113, 1273–1275.